Interpillar distance effect in a two-step microneedle DRIE process and its transfer to polymeric microneedles

Interpillar distance effect in a two-step microneedle DRIE process and its transfer to polymeric microneedles | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Interpillar distance effect in a two-step microneedle DRIE process and its transfer to polymeric microneedles Iker Rodrigo Chávez-Urbiola, Juan Ponce-Hernández, Gilberto León-Muñoz, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4308287/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract This work presents the effect of interpillar distance in a two-step DRIE process for microneedles fabrication. The two-step DRIE process consists of a pillar creation followed by the pillar etching till turning it into a needle. The effect was carried out in a dumbell-well pattern. The employed dumbell-well pattern was adjusted to produce 650 µm microneedle height. The microneedle density was fixed at 657 / cm 2 , and the interpillar distance was increased by reducing the pillar area. At a short interpillar distance, 25 µm, the etching rate is higher on the surface; for a wider distance, 75–100 µm, the etching produces triangular needles. At an interpillar distance of 200 µm or greater, the pillar etch rate becomes uniform along the microneedle height, producing a thin, sharp micropillar. The obtained silicon microneedles were employed to fabricate polymeric microneedles via micro-molding. The polymeric microneedles obtained by micro-molding showed the exact geometry of the original one. The obtained polymeric microneedles showed the capacity to penetrate the skin with a 0.5 N. Microneedles DRIE Silicon Polymeric needles Micro-molding Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1 Introduction In recent decades, research into medical devices for glucose monitoring has undergone significant advances, and among the most notable innovations is the fabrication of microneedles. These tiny structures, manufactured with micrometer-scale precision with heights from 100 µm to 900 µm, have emerged as a promising tool in the medical field to overcome the limitations associated with traditional routes [ 1 ]. Traditional routes imply a painful process or continuous discomfort. These processes are employed several times throughout a person's life span, decreasing the life quality. Microneedle technology offers a painless, promising technology that will improve the life quality of a sick person. There are various forms and methods of microneedle manufacture depending on the purpose of the microneedle; solid, hollow, and porous microneedles have been developed. There are various types of microneedles, each with its unique application. These include solid microneedles, which can be coated with a functionalized layer with specific enzymes to detect an analyte of interest, such as glucose [ 2 ]. The advantage of solid microneedles is their fabrication versatility, allowing them to be made from any material suitable for their application and coated with a range of substances from enzymatic, metallic, to biodegradable polymers. This versatility in design and application is a testament to the potential of microneedles in the field of glucose monitoring. Interstitial fluid provides analytes that can be employed to monitor a person's health, such as glucose. Interstitial fluid is in almost all live tissues, such as human skin. Human skin comprises several layers; the outer layer is the stratum corneum, a thin, lifeless protective layer without interstitial fluid; the second one is the dermis, which is characterized by the absence of nerves or veins but has an interstitial fluid. This layer presents a thickness variation according to several factors (body part, age, humidity, personal lifestyle, among others), but it can be found in a deep range of 30- 1200 µm. Therefore, the dermis provides a painless alternative to quantify analytes. The purpose of a tool defines its characteristics. To quantify interstitial glucose concentration or another analyte in interstitial fluid, reaching the required depth and piercing the stratum corneum is necessary. Therefore, microneedles present an alternative to access interstitial fluid without pain. Microneedle fabrication has been developed over the years, and there are two main ways to manufacture them: wet etching[ 3 , 4 ] or dry reactive ion etching (DRIE) [ 5 ]. The first one is wet etching, based on the silicon crystalline structure; for example, KOH produces a preferential etching on the plane (111), and HF produces an isotropic etching. On the other hand, the DRIE process produces vertical-isotropic and anisotropic etching; each etching varies according to the gas employed and the process. The DRIE process presents higher versatility over wet etching, but both depend on the mask geometry and etching steps [ 6 ]. A simple mask based on squares or circles with one isotropic etch step produces drop-like needles for solid microneedles. The same mask (squares or circles) employing two etching steps (Isotropic and anisotropic) can create an obelisk-shaped needle [ 7 ]. Another mask with circular opens on the corners of a square using two etching steps (anisotropic and isotropic) produces sharper needles but smaller needles than the obelisk-shaped needles. Assuredly, mask geometry impacts the needle shape. The last described mask can implement simple changes. A microchannel that connects the openings in the circle corners (dumbbell well feature) modifies the needle structure, but the microchannel width is randomly employed. The distance between structures and their depth is related to etching rate variation along the well-deep. A vertical etching variation can be utilized to produce complex structures. A higher etching rate on the surface will produce pyramidal structures, and a uniform etching rate will make an obelisk shape. On high aspect ratio structures (wide-deep), this vertical etching rate variation can present an opportunity to fabricate interesting needle geometries. This paper delves into the vertical etching rate variation on a high aspect ratio microneedles. High aspect ratio microneedles were fabricated with a height of ≈ 700 micrometers, varying the distance between structures employing a dumbbell-well mask. It correlates with vertical etching rate variation upon structure distance, and well depth. The produced solid microneedles can penetrate the skin until the dermis for interstitial fluid access. 2 Experiment 2.1 Fabrication of SI microneedles Initial reports about microneedles with a two-step DRIE process (anisotropic and isotropic) employed circular microwell patterns [ 8 , 9 , 10 , 11 ]. These patterns produce a bridged valley between neighboring needles; as a result, the aspect ratio is low [ 11 ]. Subsequent works are related to its modification by a microwell diameter increment and distance among them, which improves the aspect ratio and increases the pitch between needles, consequently reducing the density of the microneedle array [ 12 , 13 , 14 , 15 ]. A dumbbell well feature was employed to solve the bridged valley formation between neighboring needles, as reported by Hyeonhee Roh. The dumbbell-well pattern isolates each microneedle from the first anisotropic etching, producing micropillars [ 10 , 16 ]. The subsequent 2nd DRIE process (isotropic) turned the micropillars into sharp needles. The 2nd DRIE process shows a higher etching rate on the micropillar top than in the base; the isotropic process and the needle-pitch produce this effect [ 17 , 18 , 19 ]. In this work, we adjusted the relation well diameter and well distance to obtain a high aspect ratio microneedle with a height of 700 µm from the Hyeonhee Roh work; the resultant feature is a well diameter of 327 µm with a channel width of 25 µm. The channel width was incremented from 50 µm to 327 µm to study the vertical etching rate variation upon structure distance. The purpose of height is to employ the microneedle on dermal applications in the dermis (interstitial fluid). Figure 1 shows the complete microfabrication process to obtain microneedles. In Fig. 1 a, e, and i, the representative transfer pattern masks, varying the channel width that connects the circular wells, are schematized. The channel width was incremented to analyze the vertical etching variation; the employed channel width was 0, 50, 75, 100, and 375 µm. The channel width allows the etching gas to enter around micropillars. The distance between micropillars defines the amount of etching gas that surrounds them. As is shown in the literature, the etching rate on the top is higher than on the bottom, producing a sharp tip. As the distance between the micropillar increases, the etching rate along the height varies until it becomes uniform. Figure 1 b, f, and j show obelisks formed after the first DRIE etching process. As shown, it is possible to observe that the channel width increment results in a distance increment between pillars, but the needle density remains. In Fig. 1 c, g, and k, different geometries of microneedles were obtained following an isotropic etching process; this is done due to the geometrical mask change. Then, Fig. 1 d, h, and l show the detail of the top area of microneedles, where it is evident that a sharper edge can be achieved depending on the width of the microchannel or pillar distance. As mentioned, the microfabrication process was mainly carried out in two stages: an anisotropic and an isotropic etching. The anisotropic etching was performed in three phases. Firstly, the halocarbon polymer is deposited to protect the obelisk walls from the etching of the DRIE technique. Subsequently, using an Inductive Couple Plasma (ICP), the SF 6 ions in the DRIE chamber are aimed toward the structure's bottom, allowing a preferential etching of the base. Although the polymer layer is reduced during the etching, the uncovered or unprotected areas are preferentially etched, thus promoting the formation of obelisks according to the wall thickness defined in the mask. The hard mask was fabricated by a layer of 120 nm of chromium (e-beam process, 99.99% purity chromium pellets, 0.5 Å/s deposition rate). Then, a photolithography process with positive photoresist (S1813, 12000 Å thickness ) was performed to pattern the designs into the wafer. Due to the high aspect ratio needed to fabricate a 700 µm height structure, was used a DRIE-ICP system to etch the silicon wafer. To achieve the microneedle shape, the ion etching process was divided into two steps, anisotropic and isotropic. In the anisotropic step, the unmasked surface is passivated by the deposition of the C 4 F 8 layer, and afterward, sulfur hexafluoride (SF 6 ) and oxygen (O 2 ) are used as etching gases. An obelisk structure is achieved after several cycles. Subsequently, the isotropic step is performed by exposing the obelisk structures in a constant sulfur hexafluoride (SF 6 ) and oxygen (O 2 ) gas flow. The high aspect ratio of the structures allowed the silicon-etching rate at the top to be higher than at the bottom of the structure. On the other hand, the isotropic etching, which defines the microneedle structure, is directly correlated with the desired height and shape of the microneedles, which in this case is ≈ 700 µm. It is reported in the literature that the etching is more intense at the top of the structure, allowing the formation of a pointed edge, and less intense at the base, forming a pyramid-like structure [ 20 , 21 ]. However, when increasing the wall thickness, it is observed that the isotropic etching is more homogeneous both at the top and the base, forming a needle with a pin-like geometry. It is essential to mention that the thickness of the micro wall and the desired height of the microneedle are critical parameters to obtaining structures with a sharp tip and a pyramidal base, providing greater mechanical support than a thin microneedle structure and, considering that most applications using microneedles focus on the capacity of penetrating different surfaces without breaking. Since the isotropic etching starts at the top and as the SF 6 ions penetrate the surrounding of the obelisks, it can be observed that the etching rate is higher on the surface than at the base, especially for wider micro wall thicknesses between obelisks if the micro wall is narrow, the diffusion of SF 6 ions will be limited, and vice versa. On the other hand, it is essential to mention that if it is necessary to fabricate needles of greater height, a wider distance between pillars is also required. 2.2 Micro-molding for microneedle replication The microneedles obtained by the DRIE process result in expensive ones that are not economically viable for mass production; there is the alternative to transfer the microneedle structure to mass production via mold casting. Mold casting offers the advancement of reproducing silicon microstructures to polymers. The polymer that can be used for mold casting can be biocompatible polymers like SU8, PEG, PLA, and PCL, among others [ 22 , 23 , 24 , 25 ]. The employed mold casting process is shown in Fig. 2 . The mold casting is composed of 8 steps. The first stage is the master mold fabrication. A master mold is formed by an open cylindrical mold and a removable bottom with a pedestal in the center (Fig. 2 . a-b). The pedestal is employed to attach the produced silicon microneedles. both elements were 3D printed with high-temperature resin. These three components make the master mold. On the assembled master mold, 5 ml of RTV-615 silicone (Momentive brand) was placed at the ratios indicated by the manufacturer and cured for 1 hour at 100°C (Fig. 2 . c-d), then the resultant mold was removed from the master mold. Then de-molded (Fig. 2 . e) and proceeded to manufacture the microneedles with the following methodology: 300 ml of Omnicoat (Omnicoat tm , Micro-Chem) was poured over the microneedle pattern until completely covered, and then the excess was drained. The Omnicoat in the silicone molds was cured for 10 minutes at 95°C and then at 200°C for 1 minute. 300 ml of SU-8 -2 resin (EPON™ Resin SU-8, 45 cSt) was placed and cured for 2 hours at 65°C. It was allowed to cool at room temperature for 2 hours and subsequently cured at 95°C for 4 hours. The resin was allowed to cool for 12 hours at room temperature and then cured again for 2 hours at 95°C and allowed to cool to room temperature. The resin was then cured by ultraviolet light for 2 hours. Finally, the microneedles were demolded from the silicone mold and cured at 180°C for 2 hours (Fig. 2 . f-h). The SU-8 polymeric microneedles were metalized (e-beam process, 99.99% purity titanium pellets − 0.5 Å/s deposition rate, and 99.99% purity platinum pellets − 0.5 Å/s deposition rate), with 10 nm of titanium as an adhesion layer and 100 nm of platinum for conductive and biocompatible purposes (Fig. 2 i). 2.3 Penetration test of micromolded microneedles A penetration test was performed on a silicone skin-like patch, which is used as a skin replacement in surgical practices due to its similarity in stiffness to human skin. Models 1 and 5 were discarded from this test due to the size of their tips, which were not manufactured by micro-molding. The three models were covered with methyl violet to visualize the penetration mark on the silicone patch after penetration. Videos and photographs were taken during the penetration tests, which were later analyzed using Image J to obtain the penetration percentage of each model on the silicone skin-like patch. Whe apply 0.5 axial force for the penetration. 3 Results and discussions 3.1 Silicon microneedle characterization Five models of microneedles with different geometries are present in Fig. 3 a-e, varying the width of the microchannel, which, as mentioned before, corresponds to the gap between each obelisk before the isotropic etching. The distance between pillars is directly related to the sharpness of the microneedle. It is observed that the more separation exists between the obelisks before isotropic etching, the finer the needle becomes, but it loses structural support against lateral forces (Fig. 3 e). If the distance between the micropillar narrows, the microneedle is less sharp but thicker at the base, forming a pyramidal structure with higher resistance (Fig. 3 b). During isotropic etching, the SF 6 gas spreads more fluidly as the width of the micro-wall increases, allowing the ions to reach the contour of the obelisk and initiate etching both at the top and the base (Fig. 3 f and g). The conical or pyramidal effect is obtained not only due to the distance between micro pillars but also in accordance with the desired height of the microneedles. In this case, for a height approach to 700 µm, it is observed that the ions start etching at the top, being the most exposed area to the gas. Then, as the ions continue etching toward deeper areas, the etching rate becomes lower at the base than at the top. On the other hand, if a needle with a lower height and a wider distance between micropillars is proposed, the resulting microneedle would have a pin-like appearance, very sharp but also thin, and consequently with very low lateral resistance. Model 1 (Fig. 3 a) is a thick microneedle with a bridge valley that connects the needles is observed, and a reported elsewhere effect known as bridge-valley [ 8 , 9 , 10 , 11 ] is observed. Since in this model, there is no microchannel, the SF 6 ions start the etching at the top of the structure but are much slower as it becomes deeper; as it is an isotropic etching, the top of the microneedle is over-etched; in consequence, the microneedle loses height, sharpness, and evidence an undesired thickness. Also, microneedles are connected through the unetched structure in a bridge-valley-like geometry [ 12 ]. Model 4 (Fig. 3 d) of the microneedle presents a desirable geometry, consisting of a sharp tip and a pyramidal structure with a thickness at the base that provides mechanical resistance. Following the strategy of modulating the width of the microchannel (distance between micropillars) and the desired height of the microneedle, it is also possible to maintain the needle density, i.e., the separation between microneedles, therefore, the distance between micropillars modifies the microneedle shape. The microneedle density remains constant across the models because the micropillar center remains without modification between the models; the micropillar distance increases as the microchannel width increases; therefore, the micropillars become thinner. As mentioned, the geometry of the microneedle directly depends on the microchannel width and the desired height. In this work, it was possible to obtain microneedles with different thicknesses and sharpness. According to this work, to obtain a microneedle with desirable characteristics in sharpness and base thickness with a pyramidal geometry, the ratio between height and width of the micro-wall should be maintained, and following the two-stage etching process, first anisotropic and then isotropic. Microneedle dimensions upon interpillar distance increment are shown in Table 1 . From the table is possible to observe the parameter variation. The micropillar width decreases as the interpillar distance increment increases. This is to keep the microneedle density constant. As the interpillar distance increases become greater, the aspect ratio width/height increases from 4.6 to 15.8. The obtained needles, with a ratio of 15.8, presented a fragile structure for lateral forces. Therefore, the model for a penetration test was discarded. Micropillar width decrement results are due to the constant microneedle density and the increment of interpillar distance. The needle height is increased from 631 to 650 µm as the interpillar distance increment; the small height increment is attributed to there being less material to edge due to the micropillar decrement width. Lastly, as the interpillar distance increases, the needle shape changes from triangular to thin obelisk. Table 1 Microneedles dimension variation upon micropillar distance Model 2 Model 3 Model 4 Model 5 Interpillar distance 50 µm 75 µm 100 µm 211 µm Micropillar width 325 µm 300 µm 275 µm 245 µm Tip-Size 42.1 µm 16.8 µm 4.82 µm ~ 2 µm Microneedle Density 657 /cm 2 657 /cm 2 657 /cm 2 657 /cm 2 Aspect Ratio width/height 4.6 5.8 7.3 15.8 Needle width 137 µm 109 µm 88 µm 41 µm Needle heigth 631 µm 643 µm 646 µm 650 µm 3.2 Morphology of microneedles produced by micro-molding The molding process is shown in Fig. 4 . The microneedle set on top of the pillar is shown in Fig. 4 a. The primary objective is to provide depth to the mold, which results in the polymeric base thickness. The employed master mold is shown in Fig. 4 b; we employed a circular mold due to the advantage of unmolding the RTV – mold. Once the RTV is poured and cured, it is removed from the master mold; the obtained mold is shown in Fig. 4 c. The obtained SU-8 microneedle set exhibited a total size of 8 x 5 mm (Fig. 4 d), shows the resultant polymeric microneedles after metallización at Fig. 4 e. The obtained metallized microneedles showed a uniform coating (Fig. 4 f), which provides a conductive surface to be employed as electrodes; the application of conductive microneedles can be as electrodes for analytes like glucose and electrodes to sense the heart rate. The morphological follow-up of the resultant microneedles, composed of three stages: silicon microneedles, polymeric microneedles, and metalized polymeric microneedles. The first column, Fig. 5 a, d, and g, shows the silicon microneedles manufactured by DRIE. The rows show the suitable models for skin penetration. Model 1 and Model 5 were discarded due to their size tips. Fig. a shows Model 2 morphology. Fig. d refers to Model 3, and Fig. g shows Model 4. It can be seen how the tip gets sharper and the microneedle superior body part thinner. This effect is provided by micropillar separation; Model 2 has a narrow space of 50 µm, which results in an obelisk structure. Model 4 shows the effect of micropillar distance increment at 100 µm, where the tip formation starts at the middle of the needle high. The obtained properties are described in Table 1 . The middle column shows the SU-8 microneedles made by micro molding; Fig. b shows Model 2, where it can be observed that it maintains exactly the same morphology as the silicon microneedles; the same geometric translation to polymer material is shown in Fig. 5 e and Fig. 5 h. Therefore, the same characteristics in tip size and structure geometry can be observed. It is important to mention the absence of regular problems like not fully developed geometry in polymeric material and the bubble shape on the resultant needle. Finally, the right column shows the SU-8 microneedles metalized with Ti/Pt of Models 2, 3, and 4 in Fig. 5 c, f, and i, respectively, where it is observed the conservation and follow-up of the morphology of the original silicon microneedles because it is a quite thin metallization layer of 110 nm, but enough to be conducive for their subsequent applications as electrodes. 3.3 Penetration rate of micro-molded microneedles All three microneedles models penetrated the silicone skin-like patch with a percentage of more than 80% (Fig. 6 c) and adhered to it even in a reversed position. The needle mark on the skin silicone can be observed for all tested models. After applying an axial force, we observe a push-back effect or bounce produced by the elasticity of the skin silicone. The bounce effect was measured; Model 4, the thinner needle, presents a bounce of 5.5% of its length (Fig. 6 d). Therefore, 94.5% of its length remains inside the skin. As thicker become the needle the bounce increments for Model 3, 14.2% (Fig. 6 b) and for the thicker one, Model 2, 17% of bouncing (Fig. 6 a). 4 Conclusions The interpillar distance parameter in a two-step DRIE process for microneedle fabrication affects the microneedle shape. At a short interpillar distance (25 µm), the etching rate is higher on the surface; for a wider distance, 75–100 µm, the etching produces triangular needles. At an interpillar distance of 200 µm or greater, the pillar etch rate becomes uniform along the microneedle height, producing a thin, sharp micropillar. The obtained silicon microneedles were employed to fabricate polymeric microneedles via molding. The polymeric microneedles obtained by molding showed the exact geometry of the original one. The obtained microneedles showed the capacity to penetrate the skin and the potential to employ them as electrodes. Declarations Funding This work was supported by CONAHCYT projects FORDECYT No. 297497 and No. 322623 (LANITEM). Competing Interests The authors have no relevant financial or non-financial interests to disclose. Author Contributions All authors contributed to the study conception and design. R. Chávez-Urbiola: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Funding acquisition, Visualization, Writing - original draft, review & editing. J. Ponce-Hernández: Methodology. G. León-Muñoz: Methodology and writing. D. Fernandez Benavides: Methodology, writing and review. A. Cruz-Zabalegui: Methodology and review. J. Alcantar-Peña: Project administration. J.J. Martínez-Sanmiguel: Methodology and review. D. Díaz-Alonso: Project administration. E.J. Alvarado-Muñoz: Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, review & editing. Acknowledgments CONAHCYT financially supports this work with the projects FORDECYT No. 297497 and No. 322623 (LANITEM). References Vora LK et al (2023) Microneedle-based biosensing, Nature Reviews Bioengineering vol. 2, no. 1, pp. 64–81, Sep. 2023, 10.1038/s44222-023-00108-7 Dervisevic M, Jara Fornerod MJ, Harberts J, Zangabad PS, Voelcker NH (Feb. 2024) Wearable Microneedle Patch for Transdermal Electrochemical Monitoring of Urea in Interstitial Fluid. 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J Microelectromech Syst 21(5):1084–1089. 10.1109/JMEMS.2012.2203790 Rezali FAM, Soin N, Wan Muhamad Hatta SF, Daut MHM, Nouxman MHAH, Hussin H (2022) Design Strategies and Prospects in Developing Wearable Glucose Monitoring System Using Printable Organic Transistor and Microneedle: A Review, IEEE Sens J , vol. 22, no. 14, pp. 13785–13799, Jul. 10.1109/JSEN.2022.3181043 Supplementary Files Graphicalabstract.png Graphical abstract Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 30 Apr, 2024 Reviewers invited by journal 28 Apr, 2024 Editor assigned by journal 26 Apr, 2024 First submitted to journal 24 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4308287","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":296446216,"identity":"00d950aa-3223-4e70-a25c-93102f49a7ed","order_by":0,"name":"Iker Rodrigo Chávez-Urbiola","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Iker","middleName":"Rodrigo","lastName":"Chávez-Urbiola","suffix":""},{"id":296446217,"identity":"a060bd6a-7e5c-43f0-a1ae-f45d6e291573","order_by":1,"name":"Juan Ponce-Hernández","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Ponce-Hernández","suffix":""},{"id":296446218,"identity":"9be30b85-69fb-4f84-9dca-e582a3b73f0d","order_by":2,"name":"Gilberto León-Muñoz","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Gilberto","middleName":"","lastName":"León-Muñoz","suffix":""},{"id":296446219,"identity":"7c424c10-1c07-42b8-a0f8-ff6a08408de2","order_by":3,"name":"Alexis Cruz-Zabalegui","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Alexis","middleName":"","lastName":"Cruz-Zabalegui","suffix":""},{"id":296446220,"identity":"c08baa29-531b-41ce-93de-ca4da8649d56","order_by":4,"name":"David Fernandez-Benavides","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Fernandez-Benavides","suffix":""},{"id":296446221,"identity":"b127c4a7-479d-4a33-ab6b-6923dc14fa1b","order_by":5,"name":"Jesús Javier Alcantar-Peña","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jesús","middleName":"Javier","lastName":"Alcantar-Peña","suffix":""},{"id":296446222,"identity":"e7f01154-9162-4481-894a-bbd572d9c498","order_by":6,"name":"Juan José Martínez-Sanmiguel","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"José","lastName":"Martínez-Sanmiguel","suffix":""},{"id":296446223,"identity":"d54c0e9b-0f44-4571-beeb-e72128a30055","order_by":7,"name":"Daniela Díaz-Alonso","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Daniela","middleName":"","lastName":"Díaz-Alonso","suffix":""},{"id":296446224,"identity":"8b96d0ba-807b-4342-a4fb-dc1ab338b136","order_by":8,"name":"Estephanny Jocelyn Alvarado-Muñoz","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwklEQVRIiWNgGAWjYFCCA0BccQDCfEC8ljMHGHhAzASiLWJsg2hhIEoLP+MBxk83592Rsxc7/BBoi52cbgMBLZINB5ilc7c9M+aRTjMAakk2NjtAQIvBgQMMQC2HE3ukE0BaDiRuI6TF/sAB5t+5c0Ba0j8Qp8WA4QCbdG4DSEsOkbZIHDjYZp1z7LAxz+2cggMJBkT4hX/G4cO3c2oOy7HPTt/84UOFnRxBLQwSBxtQ3EkE4G8gqGQUjIJRMApGOgAAoWBJYc71lp4AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-0178-1537","institution":"CIDESI: Centro de Ingenieria y Desarrollo Industrial","correspondingAuthor":true,"prefix":"","firstName":"Estephanny","middleName":"Jocelyn","lastName":"Alvarado-Muñoz","suffix":""}],"badges":[],"createdAt":"2024-04-22 22:23:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4308287/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4308287/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55794304,"identity":"218ab14d-194e-43f6-90aa-6291ad17ccba","added_by":"auto","created_at":"2024-05-03 10:20:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":150543,"visible":true,"origin":"","legend":"\u003cp\u003eInterpillar distance increment effect on constant microneedle density distribution, a) well pattern, b) 1\u003csup\u003est\u003c/sup\u003e anisotropic etch on a well pattern, c) 2\u003csup\u003end\u003c/sup\u003e isotropic etch on a well pattern, d) resultant needle from a well pattern, e) bumbell-well pattern, f) 1\u003csup\u003est\u003c/sup\u003e anisotropic etch on a dumbbell-well pattern, g) 2\u003csup\u003end\u003c/sup\u003e isotropic etch on a dumbbell-well pattern, h) resultant needle from a dumbbell-well pattern, i) squared pattern, f) 1\u003csup\u003est\u003c/sup\u003e anisotropic etch on a squared pattern, g) 2\u003csup\u003end\u003c/sup\u003e isotropic etch on a squared pattern, and h) resultant needle from a squared pattern\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4308287/v1/846b9b102dad787be1425339.png"},{"id":55794308,"identity":"43e4aca1-323a-446a-99ea-030c04b951bc","added_by":"auto","created_at":"2024-05-03 10:20:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":143335,"visible":true,"origin":"","legend":"\u003cp\u003eSU-8 resin microneedle micro-molding process. a) master mold, b) Silicon assembly on a master mold, c) RTV-615 silicone in master mold, d) silicone mold disassembly from the master mold, e) RTV-615 Silicone mold, f) SU-8 resin in the silicone mold, g) SU-8 microneedle unit demolding, h) SU-8 resin microneedle unit and i) SU-8 microneedle Ti/Pt metalized.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4308287/v1/456be267da8aee04f87c7030.png"},{"id":55794307,"identity":"a8cc3320-8061-41a0-abe5-41cb82464e14","added_by":"auto","created_at":"2024-05-03 10:20:30","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":267833,"visible":true,"origin":"","legend":"\u003cp\u003eInterpillar distance effect on silicon microneedle, column a) microneedle from a well pattern, column b) dumbell-well pattern -50 µm channel width and obtained microneedle, c) dumbell-well pattern -75 µm channel width and obtained microneedle, d) dumbell-well pattern -100 µm channel width and obtained microneedle, e) squared pattern -211 mm and obtained microneedle.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4308287/v1/f67de8ddde6a4ba5e677d60f.png"},{"id":55794861,"identity":"ca83199c-e40e-4ed0-ba90-e33efd896131","added_by":"auto","created_at":"2024-05-03 10:28:30","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":403278,"visible":true,"origin":"","legend":"\u003cp\u003eResults of the micro molding and metallization process of SU-8 resin microneedle units. a) Silicon microneedles mounted on resin master mold pedestal, b) master mold, \u0026nbsp;c) RTV silicone mold, d) SU-8 resin microneedle resin unit, e) Zoom 100x on individual microneedles of the SU-8 resin microneedle unit, and f) Zoom on individual microneedles of the Ti/Pt metalized microneedle unit.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4308287/v1/ce20756e4f05fc13afb5c27d.png"},{"id":55794313,"identity":"348859f1-be0c-4a69-aadb-640d754e5edc","added_by":"auto","created_at":"2024-05-03 10:20:31","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":729463,"visible":true,"origin":"","legend":"\u003cp\u003eMorphological follow-up of the fabrication of Ti/PT metalized SU-8 microneedles by micro molding technique from silicon microneedles fabricated by DRIE. a) Model 2 of silicon microneedles, b) Model 2 of SU-8 microneedles, c) Model 2 of metalized SU-8 microneedles, d) model 3 of silicon microneedles, e) model 3 of SU-8 microneedles, f) model 3 of metalized SU-8 microneedles, g) model 4 of silicon microneedles, h) model 4 of SU-8 microneedles, i) model 4 of metalized SU-8 microneedles.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4308287/v1/0ef161fabaefac32f3fed3a6.png"},{"id":55794311,"identity":"2981aa4d-a76b-4d33-81be-8d2b06f56cc9","added_by":"auto","created_at":"2024-05-03 10:20:31","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":479132,"visible":true,"origin":"","legend":"\u003cp\u003ePenetration test on a silicone skin-like patch by applying a force of 0.5 N. a) Model 2, b) Model 3, c) Percent penetrarion graph, d) Model 4.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-4308287/v1/2282ac5678cf7a3006e81e02.png"},{"id":55794862,"identity":"0adec898-80e1-47cb-97c5-c7abf21426a4","added_by":"auto","created_at":"2024-05-03 10:28:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3389416,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4308287/v1/50a42bf7-9609-4cd0-9e91-011fc9dde305.pdf"},{"id":55794860,"identity":"8621539d-8bce-4816-849c-9180387c83a7","added_by":"auto","created_at":"2024-05-03 10:28:30","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":163592,"visible":true,"origin":"","legend":"\u003cp\u003eGraphical abstract\u003c/p\u003e","description":"","filename":"Graphicalabstract.png","url":"https://assets-eu.researchsquare.com/files/rs-4308287/v1/44408c4e0cd3bd0b32133f49.png"}],"financialInterests":"","formattedTitle":"Interpillar distance effect in a two-step microneedle DRIE process and its transfer to polymeric microneedles","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eIn recent decades, research into medical devices for glucose monitoring has undergone significant advances, and among the most notable innovations is the fabrication of microneedles. These tiny structures, manufactured with micrometer-scale precision with heights from 100 \u0026micro;m to 900 \u0026micro;m, have emerged as a promising tool in the medical field to overcome the limitations associated with traditional routes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Traditional routes imply a painful process or continuous discomfort. These processes are employed several times throughout a person's life span, decreasing the life quality. Microneedle technology offers a painless, promising technology that will improve the life quality of a sick person. There are various forms and methods of microneedle manufacture depending on the purpose of the microneedle; solid, hollow, and porous microneedles have been developed. There are various types of microneedles, each with its unique application. These include solid microneedles, which can be coated with a functionalized layer with specific enzymes to detect an analyte of interest, such as glucose [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The advantage of solid microneedles is their fabrication versatility, allowing them to be made from any material suitable for their application and coated with a range of substances from enzymatic, metallic, to biodegradable polymers. This versatility in design and application is a testament to the potential of microneedles in the field of glucose monitoring. Interstitial fluid provides analytes that can be employed to monitor a person's health, such as glucose. Interstitial fluid is in almost all live tissues, such as human skin. Human skin comprises several layers; the outer layer is the stratum corneum, a thin, lifeless protective layer without interstitial fluid; the second one is the dermis, which is characterized by the absence of nerves or veins but has an interstitial fluid. This layer presents a thickness variation according to several factors (body part, age, humidity, personal lifestyle, among others), but it can be found in a deep range of 30- 1200 \u0026micro;m. Therefore, the dermis provides a painless alternative to quantify analytes. The purpose of a tool defines its characteristics. To quantify interstitial glucose concentration or another analyte in interstitial fluid, reaching the required depth and piercing the stratum corneum is necessary. Therefore, microneedles present an alternative to access interstitial fluid without pain.\u003c/p\u003e \u003cp\u003eMicroneedle fabrication has been developed over the years, and there are two main ways to manufacture them: wet etching[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] or dry reactive ion etching (DRIE) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The first one is wet etching, based on the silicon crystalline structure; for example, KOH produces a preferential etching on the plane (111), and HF produces an isotropic etching. On the other hand, the DRIE process produces vertical-isotropic and anisotropic etching; each etching varies according to the gas employed and the process. The DRIE process presents higher versatility over wet etching, but both depend on the mask geometry and etching steps [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. A simple mask based on squares or circles with one isotropic etch step produces drop-like needles for solid microneedles. The same mask (squares or circles) employing two etching steps (Isotropic and anisotropic) can create an obelisk-shaped needle [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Another mask with circular opens on the corners of a square using two etching steps (anisotropic and isotropic) produces sharper needles but smaller needles than the obelisk-shaped needles. Assuredly, mask geometry impacts the needle shape. The last described mask can implement simple changes. A microchannel that connects the openings in the circle corners (dumbbell well feature) modifies the needle structure, but the microchannel width is randomly employed. The distance between structures and their depth is related to etching rate variation along the well-deep. A vertical etching variation can be utilized to produce complex structures. A higher etching rate on the surface will produce pyramidal structures, and a uniform etching rate will make an obelisk shape. On high aspect ratio structures (wide-deep), this vertical etching rate variation can present an opportunity to fabricate interesting needle geometries.\u003c/p\u003e \u003cp\u003eThis paper delves into the vertical etching rate variation on a high aspect ratio microneedles. High aspect ratio microneedles were fabricated with a height of \u0026asymp;\u0026thinsp;700 micrometers, varying the distance between structures employing a dumbbell-well mask. It correlates with vertical etching rate variation upon structure distance, and well depth. The produced solid microneedles can penetrate the skin until the dermis for interstitial fluid access.\u003c/p\u003e"},{"header":"2 Experiment","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Fabrication of SI microneedles\u003c/h2\u003e \u003cp\u003eInitial reports about microneedles with a two-step DRIE process (anisotropic and isotropic) employed circular microwell patterns [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. These patterns produce a bridged valley between neighboring needles; as a result, the aspect ratio is low [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Subsequent works are related to its modification by a microwell diameter increment and distance among them, which improves the aspect ratio and increases the pitch between needles, consequently reducing the density of the microneedle array [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A dumbbell well feature was employed to solve the bridged valley formation between neighboring needles, as reported by Hyeonhee Roh. The dumbbell-well pattern isolates each microneedle from the first anisotropic etching, producing micropillars [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The subsequent 2nd DRIE process (isotropic) turned the micropillars into sharp needles. The 2nd DRIE process shows a higher etching rate on the micropillar top than in the base; the isotropic process and the needle-pitch produce this effect [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this work, we adjusted the relation well diameter and well distance to obtain a high aspect ratio microneedle with a height of 700 \u0026micro;m from the Hyeonhee Roh work; the resultant feature is a well diameter of 327 \u0026micro;m with a channel width of 25 \u0026micro;m. The channel width was incremented from 50 \u0026micro;m to 327 \u0026micro;m to study the vertical etching rate variation upon structure distance. The purpose of height is to employ the microneedle on dermal applications in the dermis (interstitial fluid). Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the complete microfabrication process to obtain microneedles. In Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea, e, and i, the representative transfer pattern masks, varying the channel width that connects the circular wells, are schematized. The channel width was incremented to analyze the vertical etching variation; the employed channel width was 0, 50, 75, 100, and 375 \u0026micro;m. The channel width allows the etching gas to enter around micropillars. The distance between micropillars defines the amount of etching gas that surrounds them. As is shown in the literature, the etching rate on the top is higher than on the bottom, producing a sharp tip. As the distance between the micropillar increases, the etching rate along the height varies until it becomes uniform. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb, f, and j show obelisks formed after the first DRIE etching process. As shown, it is possible to observe that the channel width increment results in a distance increment between pillars, but the needle density remains. In Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, g, and k, different geometries of microneedles were obtained following an isotropic etching process; this is done due to the geometrical mask change. Then, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed, h, and l show the detail of the top area of microneedles, where it is evident that a sharper edge can be achieved depending on the width of the microchannel or pillar distance. As mentioned, the microfabrication process was mainly carried out in two stages: an anisotropic and an isotropic etching. The anisotropic etching was performed in three phases. Firstly, the halocarbon polymer is deposited to protect the obelisk walls from the etching of the DRIE technique. Subsequently, using an Inductive Couple Plasma (ICP), the SF\u003csub\u003e6\u003c/sub\u003e ions in the DRIE chamber are aimed toward the structure's bottom, allowing a preferential etching of the base. Although the polymer layer is reduced during the etching, the uncovered or unprotected areas are preferentially etched, thus promoting the formation of obelisks according to the wall thickness defined in the mask.\u003c/p\u003e \u003cp\u003eThe hard mask was fabricated by a layer of 120 nm of chromium (e-beam process, 99.99% purity chromium pellets, 0.5 \u0026Aring;/s deposition rate). Then, a photolithography process with positive photoresist (S1813, 12000 \u0026Aring; thickness ) was performed to pattern the designs into the wafer. Due to the high aspect ratio needed to fabricate a 700 \u0026micro;m height structure, was used a DRIE-ICP system to etch the silicon wafer. To achieve the microneedle shape, the ion etching process was divided into two steps, anisotropic and isotropic. In the anisotropic step, the unmasked surface is passivated by the deposition of the C\u003csub\u003e4\u003c/sub\u003eF\u003csub\u003e8\u003c/sub\u003e layer, and afterward, sulfur hexafluoride (SF\u003csub\u003e6\u003c/sub\u003e) and oxygen (O\u003csub\u003e2\u003c/sub\u003e) are used as etching gases. An obelisk structure is achieved after several cycles. Subsequently, the isotropic step is performed by exposing the obelisk structures in a constant sulfur hexafluoride (SF\u003csub\u003e6\u003c/sub\u003e) and oxygen (O\u003csub\u003e2\u003c/sub\u003e) gas flow. The high aspect ratio of the structures allowed the silicon-etching rate at the top to be higher than at the bottom of the structure.\u003c/p\u003e \u003cp\u003eOn the other hand, the isotropic etching, which defines the microneedle structure, is directly correlated with the desired height and shape of the microneedles, which in this case is \u0026asymp;\u0026thinsp;700 \u0026micro;m. It is reported in the literature that the etching is more intense at the top of the structure, allowing the formation of a pointed edge, and less intense at the base, forming a pyramid-like structure [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, when increasing the wall thickness, it is observed that the isotropic etching is more homogeneous both at the top and the base, forming a needle with a pin-like geometry. It is essential to mention that the thickness of the micro wall and the desired height of the microneedle are critical parameters to obtaining structures with a sharp tip and a pyramidal base, providing greater mechanical support than a thin microneedle structure and, considering that most applications using microneedles focus on the capacity of penetrating different surfaces without breaking.\u003c/p\u003e \u003cp\u003eSince the isotropic etching starts at the top and as the SF\u003csub\u003e6\u003c/sub\u003e ions penetrate the surrounding of the obelisks, it can be observed that the etching rate is higher on the surface than at the base, especially for wider micro wall thicknesses between obelisks if the micro wall is narrow, the diffusion of SF\u003csub\u003e6\u003c/sub\u003e ions will be limited, and vice versa. On the other hand, it is essential to mention that if it is necessary to fabricate needles of greater height, a wider distance between pillars is also required.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Micro-molding for microneedle replication\u003c/h2\u003e \u003cp\u003eThe microneedles obtained by the DRIE process result in expensive ones that are not economically viable for mass production; there is the alternative to transfer the microneedle structure to mass production via mold casting. Mold casting offers the advancement of reproducing silicon microstructures to polymers. The polymer that can be used for mold casting can be biocompatible polymers like SU8, PEG, PLA, and PCL, among others [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The employed mold casting process is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The mold casting is composed of 8 steps. The first stage is the master mold fabrication. A master mold is formed by an open cylindrical mold and a removable bottom with a pedestal in the center (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. a-b). The pedestal is employed to attach the produced silicon microneedles. both elements were 3D printed with high-temperature resin. These three components make the master mold. On the assembled master mold, 5 ml of RTV-615 silicone (Momentive brand) was placed at the ratios indicated by the manufacturer and cured for 1 hour at 100\u0026deg;C (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. c-d), then the resultant mold was removed from the master mold. Then de-molded (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. e) and proceeded to manufacture the microneedles with the following methodology:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e300 ml of Omnicoat (Omnicoat\u003csup\u003etm\u003c/sup\u003e, Micro-Chem) was poured over the microneedle pattern until completely covered, and then the excess was drained.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThe Omnicoat in the silicone molds was cured for 10 minutes at 95\u0026deg;C and then at 200\u0026deg;C for 1 minute.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e300 ml of SU-8 -2 resin (EPON\u0026trade; Resin SU-8, 45 cSt) was placed and cured for 2 hours at 65\u0026deg;C.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eIt was allowed to cool at room temperature for 2 hours and subsequently cured at 95\u0026deg;C for 4 hours.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThe resin was allowed to cool for 12 hours at room temperature and then cured again for 2 hours at 95\u0026deg;C and allowed to cool to room temperature.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThe resin was then cured by ultraviolet light for 2 hours.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eFinally, the microneedles were demolded from the silicone mold and cured at 180\u0026deg;C for 2 hours (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. f-h).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eThe SU-8 polymeric microneedles were metalized (e-beam process, 99.99% purity titanium pellets \u0026minus;\u0026thinsp;0.5 \u0026Aring;/s deposition rate, and 99.99% purity platinum pellets \u0026minus;\u0026thinsp;0.5 \u0026Aring;/s deposition rate), with 10 nm of titanium as an adhesion layer and 100 nm of platinum for conductive and biocompatible purposes (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ei).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Penetration test of micromolded microneedles\u003c/h2\u003e \u003cp\u003eA penetration test was performed on a silicone skin-like patch, which is used as a skin replacement in surgical practices due to its similarity in stiffness to human skin. Models 1 and 5 were discarded from this test due to the size of their tips, which were not manufactured by micro-molding. The three models were covered with methyl violet to visualize the penetration mark on the silicone patch after penetration. Videos and photographs were taken during the penetration tests, which were later analyzed using Image J to obtain the penetration percentage of each model on the silicone skin-like patch. Whe apply 0.5 axial force for the penetration.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results and discussions","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Silicon microneedle characterization\u003c/h2\u003e \u003cp\u003eFive models of microneedles with different geometries are present in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea-e, varying the width of the microchannel, which, as mentioned before, corresponds to the gap between each obelisk before the isotropic etching. The distance between pillars is directly related to the sharpness of the microneedle. It is observed that the more separation exists between the obelisks before isotropic etching, the finer the needle becomes, but it loses structural support against lateral forces (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ee). If the distance between the micropillar narrows, the microneedle is less sharp but thicker at the base, forming a pyramidal structure with higher resistance (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). During isotropic etching, the SF\u003csub\u003e6\u003c/sub\u003e gas spreads more fluidly as the width of the micro-wall increases, allowing the ions to reach the contour of the obelisk and initiate etching both at the top and the base (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ef and g). The conical or pyramidal effect is obtained not only due to the distance between micro pillars but also in accordance with the desired height of the microneedles. In this case, for a height approach to 700 \u0026micro;m, it is observed that the ions start etching at the top, being the most exposed area to the gas. Then, as the ions continue etching toward deeper areas, the etching rate becomes lower at the base than at the top. On the other hand, if a needle with a lower height and a wider distance between micropillars is proposed, the resulting microneedle would have a pin-like appearance, very sharp but also thin, and consequently with very low lateral resistance.\u003c/p\u003e \u003cp\u003eModel 1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea) is a thick microneedle with a bridge valley that connects the needles is observed, and a reported elsewhere effect known as bridge-valley [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] is observed. Since in this model, there is no microchannel, the SF\u003csub\u003e6\u003c/sub\u003e ions start the etching at the top of the structure but are much slower as it becomes deeper; as it is an isotropic etching, the top of the microneedle is over-etched; in consequence, the microneedle loses height, sharpness, and evidence an undesired thickness. Also, microneedles are connected through the unetched structure in a bridge-valley-like geometry [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Model 4 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed) of the microneedle presents a desirable geometry, consisting of a sharp tip and a pyramidal structure with a thickness at the base that provides mechanical resistance. Following the strategy of modulating the width of the microchannel (distance between micropillars) and the desired height of the microneedle, it is also possible to maintain the needle density, i.e., the separation between microneedles, therefore, the distance between micropillars modifies the microneedle shape. The microneedle density remains constant across the models because the micropillar center remains without modification between the models; the micropillar distance increases as the microchannel width increases; therefore, the micropillars become thinner.\u003c/p\u003e \u003cp\u003eAs mentioned, the geometry of the microneedle directly depends on the microchannel width and the desired height. In this work, it was possible to obtain microneedles with different thicknesses and sharpness. According to this work, to obtain a microneedle with desirable characteristics in sharpness and base thickness with a pyramidal geometry, the ratio between height and width of the micro-wall should be maintained, and following the two-stage etching process, first anisotropic and then isotropic.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMicroneedle dimensions upon interpillar distance increment are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. From the table is possible to observe the parameter variation. The micropillar width decreases as the interpillar distance increment increases. This is to keep the microneedle density constant. As the interpillar distance increases become greater, the aspect ratio width/height increases from 4.6 to 15.8. The obtained needles, with a ratio of 15.8, presented a fragile structure for lateral forces. Therefore, the model for a penetration test was discarded. Micropillar width decrement results are due to the constant microneedle density and the increment of interpillar distance. The needle height is increased from 631 to 650 \u0026micro;m as the interpillar distance increment; the small height increment is attributed to there being less material to edge due to the micropillar decrement width. Lastly, as the interpillar distance increases, the needle shape changes from triangular to thin obelisk.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMicroneedles dimension variation upon micropillar distance\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModel 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModel 3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eModel 4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eModel 5\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterpillar distance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e211 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicropillar width\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e325 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e300 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e275 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e245 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTip-Size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42.1 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.8 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.82 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e~\u0026thinsp;2 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicroneedle Density\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e657 /cm\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e657 /cm\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e657 /cm\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e657 /cm\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspect Ratio width/height\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeedle width\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e137 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e109 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e88 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeedle heigth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e631 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e643 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e646 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e650 \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Morphology of microneedles produced by micro-molding\u003c/h2\u003e \u003cp\u003eThe molding process is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The microneedle set on top of the pillar is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea. The primary objective is to provide depth to the mold, which results in the polymeric base thickness. The employed master mold is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb; we employed a circular mold due to the advantage of unmolding the RTV \u0026ndash; mold. Once the RTV is poured and cured, it is removed from the master mold; the obtained mold is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ec. The obtained SU-8 microneedle set exhibited a total size of 8 x 5 mm (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ed), shows the resultant polymeric microneedles after metallizaci\u0026oacute;n at Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ee. The obtained metallized microneedles showed a uniform coating (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ef), which provides a conductive surface to be employed as electrodes; the application of conductive microneedles can be as electrodes for analytes like glucose and electrodes to sense the heart rate.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe morphological follow-up of the resultant microneedles, composed of three stages: silicon microneedles, polymeric microneedles, and metalized polymeric microneedles. The first column, Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea, d, and g, shows the silicon microneedles manufactured by DRIE. The rows show the suitable models for skin penetration. Model 1 and Model 5 were discarded due to their size tips. Fig. a shows Model 2 morphology. Fig. d refers to Model 3, and Fig. g shows Model 4. It can be seen how the tip gets sharper and the microneedle superior body part thinner. This effect is provided by micropillar separation; Model 2 has a narrow space of 50 \u0026micro;m, which results in an obelisk structure. Model 4 shows the effect of micropillar distance increment at 100 \u0026micro;m, where the tip formation starts at the middle of the needle high. The obtained properties are described in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The middle column shows the SU-8 microneedles made by micro molding; Fig. b shows Model 2, where it can be observed that it maintains exactly the same morphology as the silicon microneedles; the same geometric translation to polymer material is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ee and Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eh. Therefore, the same characteristics in tip size and structure geometry can be observed. It is important to mention the absence of regular problems like not fully developed geometry in polymeric material and the bubble shape on the resultant needle. Finally, the right column shows the SU-8 microneedles metalized with Ti/Pt of Models 2, 3, and 4 in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec, f, and i, respectively, where it is observed the conservation and follow-up of the morphology of the original silicon microneedles because it is a quite thin metallization layer of 110 nm, but enough to be conducive for their subsequent applications as electrodes.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Penetration rate of micro-molded microneedles\u003c/h2\u003e \u003cp\u003eAll three microneedles models penetrated the silicone skin-like patch with a percentage of more than 80% (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ec) and adhered to it even in a reversed position. The needle mark on the skin silicone can be observed for all tested models. After applying an axial force, we observe a push-back effect or bounce produced by the elasticity of the skin silicone. The bounce effect was measured; Model 4, the thinner needle, presents a bounce of 5.5% of its length (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ed). Therefore, 94.5% of its length remains inside the skin. As thicker become the needle the bounce increments for Model 3, 14.2% (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eb) and for the thicker one, Model 2, 17% of bouncing (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4 Conclusions","content":"\u003cp\u003eThe interpillar distance parameter in a two-step DRIE process for microneedle fabrication affects the microneedle shape. At a short interpillar distance (25 \u0026micro;m), the etching rate is higher on the surface; for a wider distance, 75\u0026ndash;100 \u0026micro;m, the etching produces triangular needles. At an interpillar distance of 200 \u0026micro;m or greater, the pillar etch rate becomes uniform along the microneedle height, producing a thin, sharp micropillar. The obtained silicon microneedles were employed to fabricate polymeric microneedles via molding. The polymeric microneedles obtained by molding showed the exact geometry of the original one. The obtained microneedles showed the capacity to penetrate the skin and the potential to employ them as electrodes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by\u0026nbsp;CONAHCYT projects FORDECYT No. 297497 and No. 322623 (LANITEM).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eR. Ch\u0026aacute;vez-Urbiola:\u003c/strong\u003e Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Funding acquisition, Visualization, Writing - original draft, review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJ. Ponce-Hern\u0026aacute;ndez:\u003c/strong\u003e Methodology.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eG. Le\u0026oacute;n-Mu\u0026ntilde;oz:\u003c/strong\u003e Methodology and writing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD. Fernandez Benavides:\u003c/strong\u003e Methodology,\u0026nbsp;writing\u0026nbsp;and review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA. Cruz-Zabalegui:\u003c/strong\u003e Methodology and review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJ. Alcantar-Pe\u0026ntilde;a:\u003c/strong\u003e Project administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJ.J. Mart\u0026iacute;nez-Sanmiguel:\u003c/strong\u003e Methodology and review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD. D\u0026iacute;az-Alonso:\u003c/strong\u003e Project administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eE.J. Alvarado-Mu\u0026ntilde;oz:\u003c/strong\u003e Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003eCONAHCYT financially supports this work with the projects FORDECYT No. 297497 and No. 322623 (LANITEM).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVora LK et al (2023) Microneedle-based biosensing, \u003cem\u003eNature Reviews Bioengineering\u003c/em\u003e vol. 2, no. 1, pp. 64\u0026ndash;81, Sep. 2023, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s44222-023-00108-7\u003c/span\u003e\u003cspan address=\"10.1038/s44222-023-00108-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDervisevic M, Jara Fornerod MJ, Harberts J, Zangabad PS, Voelcker NH (Feb. 2024) Wearable Microneedle Patch for Transdermal Electrochemical Monitoring of Urea in Interstitial Fluid. 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The two-step DRIE process consists of a pillar creation followed by the pillar etching till turning it into a needle. The effect was carried out in a dumbell-well pattern. The employed dumbell-well pattern was adjusted to produce 650 \u0026micro;m microneedle height. The microneedle density was fixed at 657 / cm\u003csup\u003e2\u003c/sup\u003e, and the interpillar distance was increased by reducing the pillar area. At a short interpillar distance, 25 \u0026micro;m, the etching rate is higher on the surface; for a wider distance, 75\u0026ndash;100 \u0026micro;m, the etching produces triangular needles. At an interpillar distance of 200 \u0026micro;m or greater, the pillar etch rate becomes uniform along the microneedle height, producing a thin, sharp micropillar. The obtained silicon microneedles were employed to fabricate polymeric microneedles via micro-molding. The polymeric microneedles obtained by micro-molding showed the exact geometry of the original one. The obtained polymeric microneedles showed the capacity to penetrate the skin with a 0.5 N.\u003c/p\u003e","manuscriptTitle":"Interpillar distance effect in a two-step microneedle DRIE process and its transfer to polymeric microneedles","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-03 10:20:26","doi":"10.21203/rs.3.rs-4308287/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-04-30T14:06:56+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-28T21:53:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-26T08:04:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"The International Journal of Advanced Manufacturing Technology","date":"2024-04-24T10:28:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-international-journal-of-advanced-manufacturing-technology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jamt","sideBox":"Learn more about [The International Journal of Advanced Manufacturing Technology](https://www.springer.com/journal/170)","snPcode":"170","submissionUrl":"https://submission.nature.com/new-submission/170/3","title":"The International Journal of Advanced Manufacturing Technology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f6276c02-ab04-46ac-84ed-a9ae89e30ace","owner":[],"postedDate":"May 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-30T22:02:39+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-03 10:20:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4308287","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4308287","identity":"rs-4308287","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}