Fabrication and evaluation of dissolving bird-bill microneedle arrays

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We aimed to fabricate a dissolving bird-bill MN (dBB MN) with a vertical groove between two thin plate-shaped needles and evaluated its ability of transdermally deliver a large-molecular-weight insulin drug into systemic circulation. Hydrogels with various concentrations of polyvinylpyrrolidone (PVP) or sodium hyaluronate (HA) were prepared, and dBB MN arrays were fabricated by micromolding under negative pressure for potential mass production. The needle height of the dBB MN was maximum when the hydrogel was 25 w/w% PVP, with a viscosity of 8–9 Pa∙s. Furthermore, the buckling force of dBB MNs made from 25 w/w% PVP was 130.6 ± 51.0 mN, which increased to 195.6 ± 65.3 mN when insulin was added at 1 w/w%. The blood glucose concentration in diabetic rats decreased slowly and significantly after a 3-h application of the insulin-loaded dBB MN array. Therefore, the dBB MN array demonstrated sufficient ability to puncture rat skin and transdermally deliver a large-molecular-weight drug into the systemic circulation. These findings suggest that the dBB MN array holds promise as a minimal invasive drug delivery platform, with potential applications in improving patient adherence and expanding access to essential therapies, particularly in resource-limited settings. bird-bill microneedle dissolving microneedle array transdermal drug delivery biocompatible polymer polyvinylpyrrolidone Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Microneedle (MN) arrays are a physical penetration enhancement method that allows macromolecular weight and highly hydrophilic compounds to be delivered through the stratum corneum (SC) into the body. The MN array comprises hundreds of micrometer-high MNs and has the advantage of being a painless device that can be delf-administrated by patients. MNs can be classified into five types: hollow, solid, coated, dissolving, and hydrogel-forming MNs. They can be also used for diagnosis and therapeutic drug monitoring [ 1 – 3 ]. Dissolving MNs (dMNs) are fabricated from various biodegradable and biocompatible macro- and high-molecular-weight polymers such as sodium chondroitin sulfate [ 4 ], sodium hyaluronate (HA) [ 5 ], poly-γ-glutamic acid [ 6 ], polyvinyl alcohol (PVA), and polyvinyl pyrrolidone (PVP) alone or a mixture of PVA and PVP [ 7 – 9 ]. dMNs are expected to quickly dissolve in the skin after skin insertion and enable efficient and complete penetration of drugs encapsulated in the MNs across the SC. In addition, they are not associated with blood contamination because they are single-use and incinerable devices. dMNs can contribute to the spread of vaccination in areas with insufficient physicians [ 10 ]. However, the release profile of drugs from dMNs and needle hardness depends on the dissolving and degradable properties of the polymers in the skin. The needle hardness of dMNs can be improved by adding additives such as nonionic surfactants [ 11 ]; however, it generally tends to be lower than that of other types of MNs. In the case of hollow and solid MN arrays, drug dosage can be increased without changing the shape of the needle. Moreover, it is necessary to change the number of needles, needle density, and the other structural factors to increase drug dosage in the dMN array. dMNs generally have conical and pyramidical shapes, which ensure the ability of skin insertion and facilitate the manufacturing process of casting/molding to pull out the dMN from the female mold. Researchers have developed various manufacturing processes to fabricate dMNs with pointed tips without a mold. Lithography was performed to prepare maltose dMNs [ 12 ]. The prepared MNs had a high aspect ratio and different shapes but were limited to polymers and drugs that do not denature at high temperatures. Kim et al. reported a method called droplet-born air blowing, which controlled the amount of drug by the pressure and time of the droplet dispenser and formed an MN shape by blowing air [ 13 ]. Inkjet printing [ 14 ], 3D printing [ 15 ], and spray-filled molding [ 16 ] have also been reported; however, most researchers have used microcasting/micromolding. For manufacturing dMNs by molding, the polymer hydrogel should be of low viscosity enough to be poured into a female mold that replicats the MNs shape, and the tips of the dMNs should be fine and hard enough to puncture the skin. Bird-bill MNs reportedly overcome the disadvantages of coated MNs [ 17 ]. Bird-bill MNs have a vertical groove between two thin plate-shaped needles; the resulting skin insertion ability is improved, and the amount of drug that is not only coated on the needle but also filled in the vertical groove is increased. However, it is difficult to fabricate dissolving bird-bill (dBB) MNs. Therefore, we aimed to fabricate a dBB MN array by microcasting/micromolding with mass-production capability, improved skin puncture properties, and sufficient hardness for insertion into the skin. Materials and Methods Materials Biocompatible and biodegradable polymers, polyvinylpyrrolidone K90 (PVP, average molecular weight; 360,000, special grade), and sodium hyaluronate FCH-80 (HA, molecular weight; 600,000–1,000,000, cosmetic grade) to fabricate dBB MN arrays were purchased from Fujifilm Wako Pure Chemical Co. (Osaka, Japan) and Kikkoman Biochemifa Co. (Tokyo, Japan), respectively. Bovine pancreatic insulin and sodium fluorescein (FL) as model drugs were purchased from Sigma-Aldrich Co. (Tokyo, Japan). Streptozotocin (STZ) and other reagents were purchased from Fujifilm Wako Pure Chemical Co. Manufacturing of a dBB MN array A female mold from polydimethylsiloxane (PDMS) was prepared for the dBB MN array designed to have 52 needles / the base of 0.44 cm 2 with 1000 µm needle height (700 µm groove and 300 µm needle-pedestal) (original male mold, Fig. 1 a). After submerging the original mold into a container filled with PDMS resin and hardener (Sylgard® 184, Dow Chemical Co., MI, USA), the container was put under reduced pressure for 5 min using a vacuum pump Da-20D (Ulvac Kiko Inc., Miyazaki, Japan) to let the air out from PDMS and subsequently kept at 80 ˚C for 1 h. HA and PVP hydrogels were prepared at concentrations of 1–4 w/w% and 15–30 w/w%, respectively. The viscosities of the hydrogels were measured using a tuning-fork vibration viscometer SV-10 (viscosity measurement range; 0.3–10,000 mPa∙s, A&D Co., Tokyo, Japan). FL and insulin, as model drugs, were added to the hydrogels at concentrations of 0.5 w/w% and 1.0 w/w%, respectively. The insulin-loaded hydrogels were prepared under ice-cold conditions because heat was generated by mixing PVP and distilled water (DW). The hydrogel (0.8–1.0 g) was placed into the PDMS mold and vacuumed at 9.5 torr for 20 min using Da-20D. The air remaining at the tip of the needle after filling the hydrogel was not removed from inside the female mold, even after centrifugation [ 18 ]. Therefore, in this study, a vaccum process was used to fill the hydrogel in the mold. The dBB MN array was dried in a desiccator OH-3S (As One Co., Osaka, Japan) at a temperature of 25˚C and humidity of 20% for 24–48 h. The dBB MN arrays were observed under a Leica MC170 HD digital microscope (Leica Microsystems GmbH, Wetzlar, Germany). After measuring the needle height and weight, the array was stored in a desiccator. The insulin-loaded dBB MN arrays were prepared immediately before the experiments to prevent insulin denaturation. Dissolution experiments of dBB MN FL-loaded dBB MN (4% HA and 25% PVP) was placed in 50 mL phosphate-buffered saline (PBS, Sigm-Aldrich Co.) preheated at 37 ˚C. PBS solutions of 500 µL were collected at 1 min intervals until the MN array was completely dissolved. FL concentrations were assayed using a fluorescein spectrometer FP-8550 (Jasco, Tokyo, Japan). Evaluation of skin insertion capability of dBB MN The buckling forces of three types of dBB MNs, 4% HA, 25% PVP, and 25% PVP + insulin, were measured using a compression testing machine MCT-510 (Shimadzu Co., Kyoto, Japan) with a loading speed of 20.7 mN/sec and a maximum compression force of 1000 mN. The compression test was repeated thrice using a single needle and different needles. Swine skin (landrace strain) with a 2–3 mm thickness was purchased from DARD Co. (Tokyo, Japan). The skin was placed on a Kimwipe® (Nippon Paper Crecia, Co., Tokyo, Japan) and moistened with DW. FL-loaded dBB MN (25% PVP) array was punctured into the skin for 10 s. After 10, 30, 60, and 180 min, the skin surface was photographed, and the height of the needles was measured using a digital microscope. In vivo experiments with diabetic rats All animal experiments were conducted in accordance with the guidelines of the Kyushu Institute of Technology and approved by the Animal Care and Use Committee of our institution. Diabetes was induced in healthy rats (8 weeks old; Jcl:SD strain, male; CLEA Japan Inc., Tokyo, Japan), and blood glucose concentration (BGC) was measured as previously described [ 17 ]. Hair on the dorsal skin of diabetic rats induced by an intraperitoneal injection of STZ (65 mg/kg in ice-cold 20 mM sodium citrate buffer, pH: 4.6) was removed 48 h prior to the experiment. Insulin-loaded dBB MN (25% PVP) was applied to the shaved area using a spring-driven applicator (5.3 m/s, 17–19 N) and maintained for 10 s. Subsequently, the MN was fixed with surgical tape (Multipore™ Dry, 3M, MN, USA) on the skin for 6 h. The BGC in a drop of blood collected from the tail vein was measured using a Medisafe® Mini GR-102 (Terumo Co., Tokyo, Japan). To ascertain the efficacy of insulin-loaded dBB MN, BGCs of rats treated with 200 IU insulin solution (soaked in cotton) and treated with the MN array without insulin were used as controls. Results and discussion Fabrication of dBB MN arrays PVP and HA were selected as the dMN materials in this study. PVP is a water-soluble, inert, non-toxic, pH-stabile, biocompatible, and biodegradable polymer that has been widely used as an excipient in various pharmaceutical applications [ 19 ]. HA has also been established as a material for dMN fabrication [ 5 , 20 ]. The viscosity of a hydrogel varies based on its chemical structure, molecular weight, and polymer material concentration [ 21 ]. A mixture of polymers was used for the microcasting of dMN to adjust the hydrogel’s characteristics [ 8 , 21 ]. We also attempted to fabricate a dMN array using a mixture of polymers, HA, PVP, and PVA, and concluded that it was difficult to fabricate a dBB MN array using this mixture because of its geometric complexity [ 18 ]. Table 1 summarizes the needle height of the dBB MN and their viscosity at various polymer concentrations. Needle height was maximal at 4% HA (954.2 ± 8.6 µm, Fig. 1 b) and 25% PVP (982.7 ± 2.4 µm, Fig. 1 c). The shape of original male mold was well reproduced using 25% PVP; however, plate-shaped needles of 4% HA were noticeably thinner than those of the original mold (Fig. 1 a). The viscosities of 4% HA and 25% PVP were 9.4 Pa∙s and 8.5 Pa∙s, respectively. For the polymer concentrations with viscosities ≥ 10.0 Pa∙s (6% HA and 30% PVP) and ≤ 5.0 Pa∙s (2% HA and 15% PVP), the needle height was ≤ 950 µm. The needle tips did not have sharp edges when the hydrogel had a viscosity of > 10.0 Pa∙s, The viscosity of the hydrogel influenced the needle height and sharpness of the dBB MN. Therefore, the property of the hydrogel needed to fabricate the dBB MN array was found to be in the range of 8–9 Pa∙s in viscosity. Table 1 Needle height and viscosity in various concentrations of polymers Concentration [%] Needle height [µm] Viscosity [Pa∙s] HA 2 932.2 ± 4.2 1.9 4 954.2 ± 8.6 9.4 6 932.8 ± 4.0 > 10.0 PVP 15 953.6 ± 2.8 3.4 20 956.1 ± 9.6 5.4 25 982.7 ± 2.4 8.5 30 941.1 ± 3.9 > 10.0 Evaluation of dBB MN arrays The influence of water content on the performance of the dMN was measured to evaluate the dBB MN array. 4% HA and 25% PVP were heated at 85˚C for 6 h after storage in a desiccator; the resulting water contents were 6.25 ± 1.46% and 2.16 ± 1.42%, respectively. The MN height after drying decreased to 883.0 ± 8.2 µm for 4% HA and 936.3 ± 16.9 µm for 25% PVP, suggesting that 4% HA dBB MNs would be affected by the drying that occurred during long-term storage. Thereafter, we measured the needle hardness of 4% HA and 25% PVP dBB MN (Fig. 2 a). The buckling force for 4% HA and 25% PVP was 19.8 ± 11.5 mN and 130.6 ± 51.0 mN, respectively (Fig. 2 b and 2 c). The buckling force of a single dMN mixed with two polymers was reported to range from 100 mN to 480 mN, and the hardness of the dMN was sufficient to withstand the force required for skin puncture [ 11 ]. The depth of micro-holes is at least 200 µm using an optical coherence tomography device [ 11 ]. Thus, 4% HA has no skin insertion capability and may not be suitable as a base polymer for dBB MNs. Figure 3 illustrates the release profiles of FL from 4% HA and 25% PVP dBB MN arrays in PBS. The dBB MN array with 4% HA completely dissolved within 7 min, whereas the 25% PVP dBB MN array exhibited a sustained release behavior and fully dissolved within 18 min. We assumed that the high polymer concentration in the hydrogel favored the maintenance of the shape and increased the hardness of the dBB MN. Based on the results of fabrications and dissolution experiments, we decided to use 25% PVP as the material of dBB MN in the following experiments. Skin insertion and transdermal delivery capability of dBB MN arrays The skin insertion capability of dBB MN was assessed in vitro using swain skin. Figure 4 a shows the relationship between application time and needle height. The MN height decreased to 471.6 ± 54.1 µm within 10 min after insertion; subsequently, it decreased at a constant rate and was 200.4 ± 48.2 µm at 180 min. Two thin plate-shaped needles of dBB MN inserted in the SC were dissolved within approximately 10 min (Fig. 4 b), and then, not only the needle pedestal but also the base of the MN array was dissolved slowly (Fig. 4 c). The buckling force of 25% PVP with insulin (195.6 ± 65.3 mN) was 1.50 times greater than that without insulin (Fig. 2 a), which may result in insulin filling the space among PVP molecules. The time course of BGC in diabetic rats is shown in Fig. 5 . No significant difference was observed between the BGCs of rats treated with the insulin solution and those treated with MN without insulin. In contrast, BGC decreased slowly and significantly after 3 h of application of the insulin-loaded dBB MN array (p < 0.05, two-tailed Student’s t-test with dMN without insulin). The number of dMNs administered is proportional to the net weight of the MNs. By measuring the weight of the base removed from the MNs, the net weight of the dBB MNs was measured at 1.01 ± 0.14 mg. Thus, the amount of insulin in the MNs was estimated to be 10.1 µg/MNs. Although this was not sufficient to immediately decrease BGC in diabetic rats, the insulin included in the base was also delivered into the body, ultimately resulting in a reduction in BGC. Thus, the dBB MN array demonstrated sufficient ability to puncture rat skin and transdermally deliver a large-molecular-weight drug into the systemic circulation. However, it had the disadvantage of taking 3 h to reduce BGC. This issue could be addressed by optimizing the composition and concentration of biodegradable polymers. Conclusions In this study, dMNs with pointed needle tips and sufficient hardness for skin insertion were fabricated using 25% PVP, with viscosity in the range of 8–9 Pa∙s, and the BGC in diabetic rats was significantly decreased by delivering a large-molecular-weight drug, insulin, into the systemic circulation. The two plate-shaped needles dissolved quickly in the SC after producing microholes, and the drug included in the needles and the base of the dBB MN array penetrated the skin. However, the BGC did not show an immediately reduction after applying the dBB MN. This could be solved by investigating the quickly dissolution of biodegradable polymers in the skin and optimizing the needle geometry for deeper insertion into the skin. The dBB MN array offer a promising advancement in minimal invasive drug delivery systems, potentially improving patient compliance and access to therapies, particularly in underserved areas. Declarations Competing interests Ms. Amano, Mr. Takaki, Mr. Takei, Mr. Matuo, Mr. Hara, Mr, Tashiro, and Mr. Oniki declare they have no relevant financial interests. Dr. Hikima and Dr. Ito has a patent pending regarding the method of fabricating the dissolving bird-bill MN. Ethics approval All animal experiments were conducted in accordance with the guidelines of the Kyushu Institute of Technology and approved by the Animal Care and Use Committee of our institution. Funding This work was supported by the Japan Society for the Promotion of Science (KAKENHI, Grant Number 22K12846). Dr. Hikima has received a partial research support from Mishima Kosan Co. Authors contribution All authors contributed to the study conceptions and design. The experiments were completed by Ms. Amano, Mr. Takaki, and Mr. Takei. The in vivo studies were carried out by Ms. Amano. The manuscript was designed, written, and revised by Dr. Hikima and Ms. Amano. All authors read and approved the final manuscript. 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Polymers. 2021;13:3043. https://doi.org/10.3390/polym13183043 Cite Share Download PDF Status: Published Journal Publication published 09 Dec, 2024 Read the published version in Drug Delivery and Translational Research → Version 1 posted Editorial decision: Major Revisions Needed 12 Oct, 2024 Reviewers agreed at journal 03 Sep, 2024 Reviewers invited by journal 03 Sep, 2024 Editor assigned by journal 26 Aug, 2024 First submitted to journal 23 Aug, 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. We do this by developing innovative software and high quality services for the global research community. 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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-4966848","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":348786175,"identity":"d63b0f91-2a05-4167-b683-d24968d90a8c","order_by":0,"name":"Natsumi Amano","email":"","orcid":"","institution":"Kyushu Institute of Technology - Iizuka Campus: Kyushu Kogyo Daigaku - Iizuka Campus","correspondingAuthor":false,"prefix":"","firstName":"Natsumi","middleName":"","lastName":"Amano","suffix":""},{"id":348786176,"identity":"84120e05-cebd-430d-b732-866240d8ca24","order_by":1,"name":"Yuusei Takaki","email":"","orcid":"","institution":"Kyushu Institute of Technology - Iizuka Campus: Kyushu Kogyo Daigaku - Iizuka Campus","correspondingAuthor":false,"prefix":"","firstName":"Yuusei","middleName":"","lastName":"Takaki","suffix":""},{"id":348786177,"identity":"e13826b9-4c7f-4ee5-936f-0d13c9cb040f","order_by":2,"name":"Harunori Takei","email":"","orcid":"","institution":"Kyushu Institute of Technology - Iizuka Campus: Kyushu Kogyo Daigaku - Iizuka Campus","correspondingAuthor":false,"prefix":"","firstName":"Harunori","middleName":"","lastName":"Takei","suffix":""},{"id":348786178,"identity":"3d1a97b8-f474-42a4-8632-3a955dd6034c","order_by":3,"name":"Masaaki Matsuo","email":"","orcid":"","institution":"Mishima Kosan Co.","correspondingAuthor":false,"prefix":"","firstName":"Masaaki","middleName":"","lastName":"Matsuo","suffix":""},{"id":348786179,"identity":"e4635360-df35-4b79-95c1-7e0ec1b14308","order_by":4,"name":"Masaya Hara","email":"","orcid":"","institution":"Mishima Kosan Co.","correspondingAuthor":false,"prefix":"","firstName":"Masaya","middleName":"","lastName":"Hara","suffix":""},{"id":348786180,"identity":"98895839-c9de-4ef1-8468-3386bbacccb9","order_by":5,"name":"Yasunori Tashiro","email":"","orcid":"","institution":"Mishima Kosan Co.","correspondingAuthor":false,"prefix":"","firstName":"Yasunori","middleName":"","lastName":"Tashiro","suffix":""},{"id":348786181,"identity":"1508c031-bced-472b-90ff-68e1ef6df0bf","order_by":6,"name":"Takahiro Oniki","email":"","orcid":"","institution":"Mishima Kosan Co.","correspondingAuthor":false,"prefix":"","firstName":"Takahiro","middleName":"","lastName":"Oniki","suffix":""},{"id":348786182,"identity":"04c447e3-d27f-467a-9151-2fcc8d6f4453","order_by":7,"name":"Takahiro Ito","email":"","orcid":"","institution":"Kyushu Institute of Technology - Iizuka Campus: Kyushu Kogyo Daigaku - Iizuka Campus","correspondingAuthor":false,"prefix":"","firstName":"Takahiro","middleName":"","lastName":"Ito","suffix":""},{"id":348786183,"identity":"72fb0d0d-de6a-40ee-ade9-e89283006ef0","order_by":8,"name":"Tomohiro Hikima","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/klEQVRIiWNgGAWjYBACA2Y2hgMMDDYJbAwMzBAhCTDJRkhLGkyLARFaIHKHExjQtOAG5uxsiYdu1JzP42NvYDbmbfsjxz+7gfHDDwa+PFxaLJvZDhzOOXa7mI3nAHMyb5uBscSdA8ySPQxsxTgddpi94XAO2+3ENokE5sNALYkbJBIYpIF+SWzAq+XfObiWeqAW5t/4tQAdltt2AKwF5LAEA4kENgK2sCUczu1LBvrlYLPhnHPGhjNuJLZZ9hjg8cv5Y8afc77Z5cm3Nx+WeFMmJ88/I/nwjR8Vx3CGGBJgbGDigTKARh1LIEILUO0PBLuGOC2jYBSMglEwEgAAdnZTEj05KK0AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-7169-9996","institution":"Kyushu Institute of Technology - Iizuka Campus: Kyushu Kogyo Daigaku - Iizuka Campus","correspondingAuthor":true,"prefix":"","firstName":"Tomohiro","middleName":"","lastName":"Hikima","suffix":""}],"badges":[],"createdAt":"2024-08-24 02:38:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4966848/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4966848/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s13346-024-01757-w","type":"published","date":"2024-12-09T15:57:42+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":67117416,"identity":"a58c8929-bcd6-4657-94ee-65066d3d0d68","added_by":"auto","created_at":"2024-10-21 10:45:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":752671,"visible":true,"origin":"","legend":"\u003cp\u003ePhotographs of (a) bird-bill microneedle (MN) original male mold, (b) 4% HA dBB MN, and (c) 25% PVP dBB MN. The original male mold was fabricated using injection molding, as previously described [17]. dBB MNs contained 0.5 w/w% fluorescein as the model drug.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4966848/v1/f7a46d4340f6322aa2ce742b.png"},{"id":67118102,"identity":"19f6bafa-5488-4172-821d-334fc9bb0f0b","added_by":"auto","created_at":"2024-10-21 10:53:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":459114,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Comparison of buckling force for dBB MN. The compression curve at a single and different needles of (b) 4% HA and (c) 25% PVP. *; p \u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4966848/v1/774557c2a5b3cf3ee8dd06f6.png"},{"id":67118101,"identity":"f826ff26-78e1-4d96-b5df-35ebc7873b84","added_by":"auto","created_at":"2024-10-21 10:53:02","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":32774,"visible":true,"origin":"","legend":"\u003cp\u003eRelease profiles of fluorescein from (■) 4% HA and (●) 25% PVP dBB MN array. The data points represent the mean ± standard deviation of three experiments.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4966848/v1/3d7d9c6881ca86d95ab51214.png"},{"id":67117418,"identity":"2f93c734-d76a-42be-bf3e-d4b92aba34e7","added_by":"auto","created_at":"2024-10-21 10:45:02","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1930325,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Relationship of skin application time and needle height and the photographs of dBB MN array at (b) 10 min and (c) 180 min after skin insertion.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4966848/v1/e20b35dd35fbb1dca70c7727.png"},{"id":67117415,"identity":"9a6d3b45-b866-4b4d-873d-e4546dac1abe","added_by":"auto","created_at":"2024-10-21 10:45:02","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":45878,"visible":true,"origin":"","legend":"\u003cp\u003eTime courses of blood glucose concentration in diabetic rats with (●) insulin-loaded dBB MN, (■) dBB MN without insulin, and (△) insulin solution on the intact skin. The data points represent the mean ± standard deviation of six experiments. *; p \u0026lt; 0.05 compared to insulin solution at the same time-point.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4966848/v1/7a7e08787a7952019c96407e.png"},{"id":71552472,"identity":"cd41d925-5754-4d3b-aa74-6485371ae1a1","added_by":"auto","created_at":"2024-12-16 16:06:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3793084,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4966848/v1/6d54c914-a1e9-45f3-bb25-74f34e94b0b8.pdf"}],"financialInterests":"","formattedTitle":"Fabrication and evaluation of dissolving bird-bill microneedle arrays","fulltext":[{"header":"Introduction","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eMicroneedle (MN) arrays are a physical penetration enhancement method that allows macromolecular weight and highly hydrophilic compounds to be delivered through the stratum corneum (SC) into the body. The MN array comprises hundreds of micrometer-high MNs and has the advantage of being a painless device that can be delf-administrated by patients. MNs can be classified into five types: hollow, solid, coated, dissolving, and hydrogel-forming MNs. They can be also used for diagnosis and therapeutic drug monitoring [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDissolving MNs (dMNs) are fabricated from various biodegradable and biocompatible macro- and high-molecular-weight polymers such as sodium chondroitin sulfate [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], sodium hyaluronate (HA) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], poly-γ-glutamic acid [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], polyvinyl alcohol (PVA), and polyvinyl pyrrolidone (PVP) alone or a mixture of PVA and PVP [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. dMNs are expected to quickly dissolve in the skin after skin insertion and enable efficient and complete penetration of drugs encapsulated in the MNs across the SC. In addition, they are not associated with blood contamination because they are single-use and incinerable devices. dMNs can contribute to the spread of vaccination in areas with insufficient physicians [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, the release profile of drugs from dMNs and needle hardness depends on the dissolving and degradable properties of the polymers in the skin. The needle hardness of dMNs can be improved by adding additives such as nonionic surfactants [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]; however, it generally tends to be lower than that of other types of MNs. In the case of hollow and solid MN arrays, drug dosage can be increased without changing the shape of the needle. Moreover, it is necessary to change the number of needles, needle density, and the other structural factors to increase drug dosage in the dMN array.\u003c/p\u003e \u003cp\u003edMNs generally have conical and pyramidical shapes, which ensure the ability of skin insertion and facilitate the manufacturing process of casting/molding to pull out the dMN from the female mold. Researchers have developed various manufacturing processes to fabricate dMNs with pointed tips without a mold. Lithography was performed to prepare maltose dMNs [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The prepared MNs had a high aspect ratio and different shapes but were limited to polymers and drugs that do not denature at high temperatures. Kim et al. reported a method called droplet-born air blowing, which controlled the amount of drug by the pressure and time of the droplet dispenser and formed an MN shape by blowing air [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Inkjet printing [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], 3D printing [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and spray-filled molding [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] have also been reported; however, most researchers have used microcasting/micromolding. For manufacturing dMNs by molding, the polymer hydrogel should be of low viscosity enough to be poured into a female mold that replicats the MNs shape, and the tips of the dMNs should be fine and hard enough to puncture the skin.\u003c/p\u003e \u003cp\u003eBird-bill MNs reportedly overcome the disadvantages of coated MNs [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Bird-bill MNs have a vertical groove between two thin plate-shaped needles; the resulting skin insertion ability is improved, and the amount of drug that is not only coated on the needle but also filled in the vertical groove is increased. However, it is difficult to fabricate dissolving bird-bill (dBB) MNs. Therefore, we aimed to fabricate a dBB MN array by microcasting/micromolding with mass-production capability, improved skin puncture properties, and sufficient hardness for insertion into the skin.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eMaterials\u003c/h2\u003e \u003cp\u003eBiocompatible and biodegradable polymers, polyvinylpyrrolidone K90 (PVP, average molecular weight; 360,000, special grade), and sodium hyaluronate FCH-80 (HA, molecular weight; 600,000\u0026ndash;1,000,000, cosmetic grade) to fabricate dBB MN arrays were purchased from Fujifilm Wako Pure Chemical Co. (Osaka, Japan) and Kikkoman Biochemifa Co. (Tokyo, Japan), respectively. Bovine pancreatic insulin and sodium fluorescein (FL) as model drugs were purchased from Sigma-Aldrich Co. (Tokyo, Japan). Streptozotocin (STZ) and other reagents were purchased from Fujifilm Wako Pure Chemical Co.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eManufacturing of a dBB MN array\u003c/h2\u003e \u003cp\u003eA female mold from polydimethylsiloxane (PDMS) was prepared for the dBB MN array designed to have 52 needles / the base of 0.44 cm\u003csup\u003e2\u003c/sup\u003e with 1000 \u0026micro;m needle height (700 \u0026micro;m groove and 300 \u0026micro;m needle-pedestal) (original male mold, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). After submerging the original mold into a container filled with PDMS resin and hardener (Sylgard\u0026reg; 184, Dow Chemical Co., MI, USA), the container was put under reduced pressure for 5 min using a vacuum pump Da-20D (Ulvac Kiko Inc., Miyazaki, Japan) to let the air out from PDMS and subsequently kept at 80 ˚C for 1 h.\u003c/p\u003e \u003cp\u003eHA and PVP hydrogels were prepared at concentrations of 1\u0026ndash;4 w/w% and 15\u0026ndash;30 w/w%, respectively. The viscosities of the hydrogels were measured using a tuning-fork vibration viscometer SV-10 (viscosity measurement range; 0.3\u0026ndash;10,000 mPa∙s, A\u0026amp;D Co., Tokyo, Japan). FL and insulin, as model drugs, were added to the hydrogels at concentrations of 0.5 w/w% and 1.0 w/w%, respectively. The insulin-loaded hydrogels were prepared under ice-cold conditions because heat was generated by mixing PVP and distilled water (DW). The hydrogel (0.8\u0026ndash;1.0 g) was placed into the PDMS mold and vacuumed at 9.5 torr for 20 min using Da-20D. The air remaining at the tip of the needle after filling the hydrogel was not removed from inside the female mold, even after centrifugation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Therefore, in this study, a vaccum process was used to fill the hydrogel in the mold. The dBB MN array was dried in a desiccator OH-3S (As One Co., Osaka, Japan) at a temperature of 25˚C and humidity of 20% for 24\u0026ndash;48 h. The dBB MN arrays were observed under a Leica MC170 HD digital microscope (Leica Microsystems GmbH, Wetzlar, Germany). After measuring the needle height and weight, the array was stored in a desiccator. The insulin-loaded dBB MN arrays were prepared immediately before the experiments to prevent insulin denaturation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDissolution experiments of dBB MN\u003c/h2\u003e \u003cp\u003eFL-loaded dBB MN (4% HA and 25% PVP) was placed in 50 mL phosphate-buffered saline (PBS, Sigm-Aldrich Co.) preheated at 37 ˚C. PBS solutions of 500 \u0026micro;L were collected at 1 min intervals until the MN array was completely dissolved. FL concentrations were assayed using a fluorescein spectrometer FP-8550 (Jasco, Tokyo, Japan).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eEvaluation of skin insertion capability of dBB MN\u003c/h2\u003e \u003cp\u003eThe buckling forces of three types of dBB MNs, 4% HA, 25% PVP, and 25% PVP\u0026thinsp;+\u0026thinsp;insulin, were measured using a compression testing machine MCT-510 (Shimadzu Co., Kyoto, Japan) with a loading speed of 20.7 mN/sec and a maximum compression force of 1000 mN. The compression test was repeated thrice using a single needle and different needles.\u003c/p\u003e \u003cp\u003eSwine skin (landrace strain) with a 2\u0026ndash;3 mm thickness was purchased from DARD Co. (Tokyo, Japan). The skin was placed on a Kimwipe\u0026reg; (Nippon Paper Crecia, Co., Tokyo, Japan) and moistened with DW. FL-loaded dBB MN (25% PVP) array was punctured into the skin for 10 s. After 10, 30, 60, and 180 min, the skin surface was photographed, and the height of the needles was measured using a digital microscope.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIn vivo\u003c/b\u003e \u003cb\u003eexperiments with diabetic rats\u003c/b\u003e\u003c/p\u003e \u003cp\u003e All animal experiments were conducted in accordance with the guidelines of the Kyushu Institute of Technology and approved by the Animal Care and Use Committee of our institution.\u003c/p\u003e \u003cp\u003eDiabetes was induced in healthy rats (8 weeks old; Jcl:SD strain, male; CLEA Japan Inc., Tokyo, Japan), and blood glucose concentration (BGC) was measured as previously described [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Hair on the dorsal skin of diabetic rats induced by an intraperitoneal injection of STZ (65 mg/kg in ice-cold 20 mM sodium citrate buffer, pH: 4.6) was removed 48 h prior to the experiment. Insulin-loaded dBB MN (25% PVP) was applied to the shaved area using a spring-driven applicator (5.3 m/s, 17\u0026ndash;19 N) and maintained for 10 s. Subsequently, the MN was fixed with surgical tape (Multipore\u0026trade; Dry, 3M, MN, USA) on the skin for 6 h. The BGC in a drop of blood collected from the tail vein was measured using a Medisafe\u0026reg; Mini GR-102 (Terumo Co., Tokyo, Japan). To ascertain the efficacy of insulin-loaded dBB MN, BGCs of rats treated with 200 IU insulin solution (soaked in cotton) and treated with the MN array without insulin were used as controls.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results and discussion","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eFabrication of dBB MN arrays\u003c/h2\u003e \u003cp\u003ePVP and HA were selected as the dMN materials in this study. PVP is a water-soluble, inert, non-toxic, pH-stabile, biocompatible, and biodegradable polymer that has been widely used as an excipient in various pharmaceutical applications [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. HA has also been established as a material for dMN fabrication [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The viscosity of a hydrogel varies based on its chemical structure, molecular weight, and polymer material concentration [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A mixture of polymers was used for the microcasting of dMN to adjust the hydrogel\u0026rsquo;s characteristics [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. We also attempted to fabricate a dMN array using a mixture of polymers, HA, PVP, and PVA, and concluded that it was difficult to fabricate a dBB MN array using this mixture because of its geometric complexity [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the needle height of the dBB MN and their viscosity at various polymer concentrations. Needle height was maximal at 4% HA (954.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6 \u0026micro;m, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb) and 25% PVP (982.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4 \u0026micro;m, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). The shape of original male mold was well reproduced using 25% PVP; however, plate-shaped needles of 4% HA were noticeably thinner than those of the original mold (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). The viscosities of 4% HA and 25% PVP were 9.4 Pa∙s and 8.5 Pa∙s, respectively. For the polymer concentrations with viscosities\u0026thinsp;\u0026ge;\u0026thinsp;10.0 Pa∙s (6% HA and 30% PVP) and \u0026le;\u0026thinsp;5.0 Pa∙s (2% HA and 15% PVP), the needle height was \u0026le;\u0026thinsp;950 \u0026micro;m. The needle tips did not have sharp edges when the hydrogel had a viscosity of \u0026gt;\u0026thinsp;10.0 Pa∙s, The viscosity of the hydrogel influenced the needle height and sharpness of the dBB MN. Therefore, the property of the hydrogel needed to fabricate the dBB MN array was found to be in the range of 8\u0026ndash;9 Pa∙s in viscosity.\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\u003eNeedle height and viscosity in various concentrations of polymers\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\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\u003eConcentration [%]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeedle height [\u0026micro;m]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eViscosity [Pa∙s]\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eHA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e932.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e954.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e932.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;10.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003ePVP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e953.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e956.1\u0026thinsp;\u0026plusmn;\u0026thinsp;9.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e982.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e941.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;10.0\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=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eEvaluation of dBB MN arrays\u003c/h2\u003e \u003cp\u003eThe influence of water content on the performance of the dMN was measured to evaluate the dBB MN array. 4% HA and 25% PVP were heated at 85˚C for 6 h after storage in a desiccator; the resulting water contents were 6.25\u0026thinsp;\u0026plusmn;\u0026thinsp;1.46% and 2.16\u0026thinsp;\u0026plusmn;\u0026thinsp;1.42%, respectively. The MN height after drying decreased to 883.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2 \u0026micro;m for 4% HA and 936.3\u0026thinsp;\u0026plusmn;\u0026thinsp;16.9 \u0026micro;m for 25% PVP, suggesting that 4% HA dBB MNs would be affected by the drying that occurred during long-term storage. Thereafter, we measured the needle hardness of 4% HA and 25% PVP dBB MN (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The buckling force for 4% HA and 25% PVP was 19.8\u0026thinsp;\u0026plusmn;\u0026thinsp;11.5 mN and 130.6\u0026thinsp;\u0026plusmn;\u0026thinsp;51.0 mN, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). The buckling force of a single dMN mixed with two polymers was reported to range from 100 mN to 480 mN, and the hardness of the dMN was sufficient to withstand the force required for skin puncture [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The depth of micro-holes is at least 200 \u0026micro;m using an optical coherence tomography device [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Thus, 4% HA has no skin insertion capability and may not be suitable as a base polymer for dBB MNs.\u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e illustrates the release profiles of FL from 4% HA and 25% PVP dBB MN arrays in PBS. The dBB MN array with 4% HA completely dissolved within 7 min, whereas the 25% PVP dBB MN array exhibited a sustained release behavior and fully dissolved within 18 min. We assumed that the high polymer concentration in the hydrogel favored the maintenance of the shape and increased the hardness of the dBB MN. Based on the results of fabrications and dissolution experiments, we decided to use 25% PVP as the material of dBB MN in the following experiments.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSkin insertion and transdermal delivery capability of dBB MN arrays\u003c/h2\u003e \u003cp\u003eThe skin insertion capability of dBB MN was assessed \u003cem\u003ein vitro\u003c/em\u003e using swain skin. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea shows the relationship between application time and needle height. The MN height decreased to 471.6\u0026thinsp;\u0026plusmn;\u0026thinsp;54.1 \u0026micro;m within 10 min after insertion; subsequently, it decreased at a constant rate and was 200.4\u0026thinsp;\u0026plusmn;\u0026thinsp;48.2 \u0026micro;m at 180 min. Two thin plate-shaped needles of dBB MN inserted in the SC were dissolved within approximately 10 min (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb), and then, not only the needle pedestal but also the base of the MN array was dissolved slowly (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003eThe buckling force of 25% PVP with insulin (195.6\u0026thinsp;\u0026plusmn;\u0026thinsp;65.3 mN) was 1.50 times greater than that without insulin (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea), which may result in insulin filling the space among PVP molecules. The time course of BGC in diabetic rats is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. No significant difference was observed between the BGCs of rats treated with the insulin solution and those treated with MN without insulin. In contrast, BGC decreased slowly and significantly after 3 h of application of the insulin-loaded dBB MN array (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, two-tailed Student\u0026rsquo;s t-test with dMN without insulin). The number of dMNs administered is proportional to the net weight of the MNs. By measuring the weight of the base removed from the MNs, the net weight of the dBB MNs was measured at 1.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14 mg. Thus, the amount of insulin in the MNs was estimated to be 10.1 \u0026micro;g/MNs. Although this was not sufficient to immediately decrease BGC in diabetic rats, the insulin included in the base was also delivered into the body, ultimately resulting in a reduction in BGC. Thus, the dBB MN array demonstrated sufficient ability to puncture rat skin and transdermally deliver a large-molecular-weight drug into the systemic circulation. However, it had the disadvantage of taking 3 h to reduce BGC. This issue could be addressed by optimizing the composition and concentration of biodegradable polymers.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this study, dMNs with pointed needle tips and sufficient hardness for skin insertion were fabricated using 25% PVP, with viscosity in the range of 8\u0026ndash;9 Pa∙s, and the BGC in diabetic rats was significantly decreased by delivering a large-molecular-weight drug, insulin, into the systemic circulation. The two plate-shaped needles dissolved quickly in the SC after producing microholes, and the drug included in the needles and the base of the dBB MN array penetrated the skin. However, the BGC did not show an immediately reduction after applying the dBB MN. This could be solved by investigating the quickly dissolution of biodegradable polymers in the skin and optimizing the needle geometry for deeper insertion into the skin. The dBB MN array offer a promising advancement in minimal invasive drug delivery systems, potentially improving patient compliance and access to therapies, particularly in underserved areas.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eMs. Amano, Mr. Takaki, Mr. Takei, Mr. Matuo, Mr. Hara, Mr, Tashiro, and Mr. Oniki declare they have no relevant financial interests. Dr. Hikima and Dr. Ito has a patent pending regarding the method of fabricating the dissolving bird-bill MN.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003eAll animal experiments were conducted in accordance with the guidelines of the Kyushu Institute of Technology and approved by the Animal Care and Use Committee of our institution.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by the Japan Society for the Promotion of Science (KAKENHI, Grant Number 22K12846). Dr. Hikima has received a partial research support from Mishima Kosan Co.\u003c/p\u003e\u003ch2\u003eAuthors contribution\u003c/h2\u003e \u003cp\u003eAll authors contributed to the study conceptions and design. The experiments were completed by Ms. Amano, Mr. Takaki, and Mr. Takei. The \u003cem\u003ein vivo\u003c/em\u003e studies were carried out by Ms. Amano. The manuscript was designed, written, and revised by Dr. Hikima and Ms. Amano. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e \u003cp\u003eThis work was supported by the Japan Society for the Promotion of Science (JSPS), KAKENHI, Grant Number 22K12846.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTuan-Mahmood TM, McCrudden MTC, Torrisi BM, McAlister E, Garland MJ, Singh TRR, Donnelly RF. Microneedles for intradermal and transdermal drug delivery. Eur J Pharm Sci. 2013;50:623\u0026ndash;7. https://doi.org/10.1016/j.ejps.2013.05.005\u003c/li\u003e\n\u003cli\u003eWaghule T, Singhvi G, Dubey SK, Pandey MM, Gupta G, Singh M, Dua K. Microneedles: A smart approach and increasing potential for transdermal drug delivery system. 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Proceeding of the 20\u003csup\u003eth\u003c/sup\u003e International Conference on Precision Engineering (ICPE2024 in Sendai). 2024.\u003c/li\u003e\n\u003cli\u003eKurakula M, Rao K. Pharmaceutical assessment of polyvinylpyrrolidone (PVP): As excipient from conventional to controlled delivery systems with a spotlight on COVID-19 inhibition. J Drug Deliv Sci Technol. 2020;60:102046. https://doi.org/10.1016/j.jddst.2020.102046\u003c/li\u003e\n\u003cli\u003eYu M, Lu Z, Shi Y, Du Y, Chen X, Kong M. Systematic comparisons of dissolving and swelling hyaluronic acid microneedles in transdermal drug delivery. Int J Biol Macromol. 2021:191:783\u0026ndash;91. https://doi.org/10.1016/j.ijbiomac.2021.09.161\u003c/li\u003e\n\u003cli\u003eYan Q, Weng J, Shen S, Wang Y, Fang M, Zheng G, Yang Q, Yang G. Finite element analysis for biodegradable dissolving microneedle materials on skin puncture and mechanical performance evaluation. Polymers. 2021;13:3043. https://doi.org/10.3390/polym13183043\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"drug-delivery-and-translational-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddtr","sideBox":"Learn more about [Drug Delivery and Translational Research](https://www.springer.com/journal/13346)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ddtr/default.aspx","title":"Drug Delivery and Translational Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"bird-bill microneedle, dissolving microneedle array, transdermal drug delivery, biocompatible polymer, polyvinylpyrrolidone","lastPublishedDoi":"10.21203/rs.3.rs-4966848/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4966848/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCoated microneedles (MNs) have some disadvantages, such as low mechanical strength, the risk of clogging and infection due to repeated application, and denaturation at high temperatures. We aimed to fabricate a dissolving bird-bill MN (dBB MN) with a vertical groove between two thin plate-shaped needles and evaluated its ability of transdermally deliver a large-molecular-weight insulin drug into systemic circulation. Hydrogels with various concentrations of polyvinylpyrrolidone (PVP) or sodium hyaluronate (HA) were prepared, and dBB MN arrays were fabricated by micromolding under negative pressure for potential mass production. The needle height of the dBB MN was maximum when the hydrogel was 25 w/w% PVP, with a viscosity of 8\u0026ndash;9 Pa∙s. Furthermore, the buckling force of dBB MNs made from 25 w/w% PVP was 130.6\u0026thinsp;\u0026plusmn;\u0026thinsp;51.0 mN, which increased to 195.6\u0026thinsp;\u0026plusmn;\u0026thinsp;65.3 mN when insulin was added at 1 w/w%. The blood glucose concentration in diabetic rats decreased slowly and significantly after a 3-h application of the insulin-loaded dBB MN array. Therefore, the dBB MN array demonstrated sufficient ability to puncture rat skin and transdermally deliver a large-molecular-weight drug into the systemic circulation. These findings suggest that the dBB MN array holds promise as a minimal invasive drug delivery platform, with potential applications in improving patient adherence and expanding access to essential therapies, particularly in resource-limited settings.\u003c/p\u003e","manuscriptTitle":"Fabrication and evaluation of dissolving bird-bill microneedle arrays","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-21 10:44:57","doi":"10.21203/rs.3.rs-4966848/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2024-10-12T11:59:03+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-09-03T08:01:36+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-03T07:40:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-26T07:43:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"Drug Delivery and Translational Research","date":"2024-08-23T22:37:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"drug-delivery-and-translational-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddtr","sideBox":"Learn more about [Drug Delivery and Translational Research](https://www.springer.com/journal/13346)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ddtr/default.aspx","title":"Drug Delivery and Translational Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8f489fb6-652e-414c-a647-f6829436d6aa","owner":[],"postedDate":"October 21st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-16T16:02:13+00:00","versionOfRecord":{"articleIdentity":"rs-4966848","link":"https://doi.org/10.1007/s13346-024-01757-w","journal":{"identity":"drug-delivery-and-translational-research","isVorOnly":false,"title":"Drug Delivery and Translational Research"},"publishedOn":"2024-12-09 15:57:42","publishedOnDateReadable":"December 9th, 2024"},"versionCreatedAt":"2024-10-21 10:44:57","video":"","vorDoi":"10.1007/s13346-024-01757-w","vorDoiUrl":"https://doi.org/10.1007/s13346-024-01757-w","workflowStages":[]},"version":"v1","identity":"rs-4966848","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4966848","identity":"rs-4966848","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}