{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:44:03Z","timestamp":1791819843374,"version":"4.3.4"},"reference-count":31,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,25]],"date-time":"2025-01-25T00:00:00Z","timestamp":1737763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Objectives: This work aimed at investigating the effect of different microneedle-based strategies on the permeation of high-molecular-weight model molecules (fluorescently labeled dextrans (FDs), 70 and 150 kDa) across the buccal mucosa. Methods: Two different approaches were evaluated: (1) stainless steel microneedles (MNs) of 500 \u00b5m height used for tissue pre-treatment; and (2) soluble microneedles of different lengths (150, 500, and 800 \u00b5m), made of polyvinylpyrrolidone and FDs, prepared using the solvent casting technique. Porcine esophageal epithelium was used as a model for the buccal mucosa. Results: The application of soluble MNs promoted high-molecular-weight dextran transport across pig esophageal epithelium. The transport was proportional to MN length, with a minimum of 500 \u00b5m, regardless of the molecular weight of the FDs. The use of solid MNs of the same length to pre-treat the tissue, followed by the application of a solution of the permeant, did not produce the same effect in terms of onset of permeation, which was found to be much slower. Conclusions: The results obtained show that by applying soluble MNs of appropriate length (500 and 800 \u00b5m), the transport of high-molecular-weight dextrans (70 and 150 kDa) across and into the mucosal tissue occurs very rapidly. The multiphoton microscopy analysis confirmed the presence of holes in the tissue and the presence of fluorescein-labeled dextrans.<\/jats:p>","DOI":"10.3390\/ph18020158","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T04:59:10Z","timestamp":1737953950000},"page":"158","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Application of Microneedles for High-Molecular-Weight Dextran Penetration Across the Buccal Mucosa"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9135-1145","authenticated-orcid":false,"given":"Adriana","family":"Fantini","sequence":"first","affiliation":[{"name":"ADDRes Lab, Department of Food and Drug, University of Parma, Parco Area delle Scienze 27\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9529-5793","authenticated-orcid":false,"given":"Andrea","family":"Delledonne","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Life Science and Environmental Sustainability, University of Parma, Parco Area delle Scienze 17\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9508-7222","authenticated-orcid":false,"given":"Luca","family":"Casula","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6955-0957","authenticated-orcid":false,"given":"Sara","family":"Nicoli","sequence":"additional","affiliation":[{"name":"ADDRes Lab, Department of Food and Drug, University of Parma, Parco Area delle Scienze 27\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6131-4375","authenticated-orcid":false,"given":"Silvia","family":"Pescina","sequence":"additional","affiliation":[{"name":"ADDRes Lab, Department of Food and Drug, University of Parma, Parco Area delle Scienze 27\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2788-7823","authenticated-orcid":false,"given":"Maria Cristina","family":"Cardia","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9858-5273","authenticated-orcid":false,"given":"Francesco","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1972-1281","authenticated-orcid":false,"given":"Cristina","family":"Sissa","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Life Science and Environmental Sustainability, University of Parma, Parco Area delle Scienze 17\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7601-7894","authenticated-orcid":false,"given":"Patrizia","family":"Santi","sequence":"additional","affiliation":[{"name":"ADDRes Lab, Department of Food and Drug, University of Parma, Parco Area delle Scienze 27\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Padula","sequence":"additional","affiliation":[{"name":"ADDRes Lab, Department of Food and Drug, University of Parma, Parco Area delle Scienze 27\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.jconrel.2022.10.059","article-title":"Oromucosal delivery of macromolecules: Challenges and recent developments to improve bioavailability","volume":"352","author":"Thu","year":"2022","journal-title":"J. Control. Release"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"de la Torre, B.G., and Albericio, F. (2024). The Pharmaceutical Industry in 2023: An Analysis of FDA Drug Approvals from the Perspective of Molecules. Molecules, 29.","DOI":"10.20944\/preprints202401.0523.v1"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"391","DOI":"10.2174\/0122117385265979231115074255","article-title":"Challenges and Therapeutic Approaches for the Protein Delivery System: A Review","volume":"12","author":"Jena","year":"2024","journal-title":"Pharm. Nanotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jconrel.2005.01.024","article-title":"Buccal penetration enhancers\u2014How do they really work?","volume":"105","author":"Nicolazzo","year":"2005","journal-title":"J. Control. Release"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"254","DOI":"10.3109\/03639040903117348","article-title":"Critical evaluation of permeation enhancers for oral mucosal drug delivery","volume":"36","author":"Sohi","year":"2010","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Padula, C., Pescina, S., Nicoli, S., and Santi, P. (2018). New Insights on the Mechanism of Fatty Acids as Buccal Permeation Enhancers. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10040201"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Fantini, A., Giulio, L., Delledonne, A., Pescina, S., Sissa, C., Nicoli, S., Santi, P., and Padula, C. (2022). Buccal Permeation of Polysaccharide High Molecular Weight Compounds: Effect of Chemical Permeation Enhancers. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15010129"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1007\/s13346-021-00909-6","article-title":"Enhancement strategies for transdermal drug delivery systems: Current trends and applications","volume":"12","author":"Ramadon","year":"2022","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_9","unstructured":"Gerstel, M.S., and Place, V.A. (1976). Drug Delivery Device. (US3964482), U.S. Patent."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jconrel.2017.11.048","article-title":"Microneedles as the technique of drug delivery enhancement in diverse organs and tissues","volume":"270","author":"Rzhevskiy","year":"2018","journal-title":"J. Control. Release"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Dsouza, L., Ghate, V.M., and Lewis, S.A. (2020). Derma rollers in therapy: The transition from cosmetics to transdermal drug delivery. Biomed. Microdevices, 22.","DOI":"10.1007\/s10544-020-00530-3"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1016\/j.biopha.2018.10.078","article-title":"Microneedles: A smart approach and increasing potential for transdermal drug delivery system","volume":"109","author":"Waghule","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"De Martino, S., Battisti, M., Napolitano, F., Palladino, A., Serpico, L., Amendola, E., Martone, A., De Girolamo, P., Squillace, A., and Dardano, P. (2022). Effect of microneedles shape on skin penetration and transdermal drug administration. Biomater. Adv., 142.","DOI":"10.1016\/j.bioadv.2022.213169"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"320","DOI":"10.3390\/macromol4020019","article-title":"Microneedles\u2019 Device: Design, Fabrication, and Applications","volume":"4","author":"Oliveira","year":"2024","journal-title":"Macromol"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.mattod.2022.10.025","article-title":"Design principles of microneedles for drug delivery and sampling applications","volume":"63","author":"Le","year":"2023","journal-title":"Mater. Today"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1080\/10611860802472370","article-title":"Optimizing microneedle arrays for transdermal drug delivery: Extension to non-square distribution of microneedles","volume":"17","author":"Das","year":"2009","journal-title":"J. Drug Target."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1080\/17425247.2023.2264189","article-title":"Microneedles for oral mucosal delivery\u2014Current trends and perspective on future directions","volume":"20","author":"Ferreira","year":"2023","journal-title":"Expert. Opin. Drug Deliv."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.jconrel.2024.01.062","article-title":"Oral mucosal vaccination using integrated fiber microneedles","volume":"367","author":"Creighton","year":"2024","journal-title":"J. Control. Release"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"eabe2620","DOI":"10.1126\/sciadv.abe2620","article-title":"A microneedle platform for buccal macromolecule delivery","volume":"7","author":"Kim","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Pireddu, R., Schlich, M., Marceddu, S., Valenti, D., Pini, E., Fadda, A.M., Lai, F., and Sinico, C. (2020). Nanosuspensions and Microneedles Roller as a Combined Approach to Enhance Diclofenac Topical Bioavailability. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12121140"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1002\/cre2.305","article-title":"Mechanical properties of human oral mucosa tissues are site dependent: A combined biomechanical, histological and ultrastructural approach","volume":"6","author":"Choi","year":"2020","journal-title":"Clin. Exp. Dent. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Farhat, W., Chatelain, F., Marret, A., Faivre, L., Arakelian, L., Cattan, P., and Fuchs, A. (2021). Trends in 3D bioprinting for esophageal tissue repair and reconstruction. Biomaterials, 267.","DOI":"10.1016\/j.biomaterials.2020.120465"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"122991","DOI":"10.1016\/j.ijpharm.2023.122991","article-title":"Buccal mucosal application of dissolvable microneedle patch containing photosensitizer provides effective localized delivery and phototherapy against oral carcinoma","volume":"640","author":"Manimaran","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.1002\/jps.20409","article-title":"Evaluation of pig esophageal mucosa as a permeability barrier model for buccal tissue","volume":"94","author":"Pizzolato","year":"2005","journal-title":"J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.jconrel.2006.11.009","article-title":"Assembled microneedle arrays enhance the transport of compounds varying over a large range of molecular weight across human dermatomed skin","volume":"117","author":"Verbaan","year":"2007","journal-title":"J. Control. Release"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Bisgaard, S.I., Nguyen, L.Q., B\u00f8gh, K.L., and Keller, S.S. (2023). Dermal tissue penetration of in-plane silicon microneedles evaluated in skin-simulating hydrogel, rat skin and porcine skin. Biomater. Adv., 155.","DOI":"10.1016\/j.bioadv.2023.213659"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1021\/js960352x","article-title":"Size-dependent dextran transport across rat alveolar epithelial cell monolayers","volume":"86","author":"Matsukawa","year":"1997","journal-title":"J. Pharm. Sci."},{"key":"ref_28","first-page":"1181","article-title":"Diffusion of high molecular weight compounds through sclera","volume":"41","author":"Ambati","year":"2000","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4202","DOI":"10.1039\/D0TB00021C","article-title":"Influence of molecular weight on transdermal delivery of model macromolecules using hydrogel-forming microneedles: Potential to enhance the administration of novel low molecular weight biotherapeutics","volume":"8","author":"Hutton","year":"2020","journal-title":"J. Mater. Chem. B"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.archoralbio.2005.04.008","article-title":"Comparison of the lipid composition of porcine buccal and esophageal permeability barriers","volume":"50","author":"Jacques","year":"2005","journal-title":"Arch. Oral Biol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Casula, L., Pireddu, R., Cardia, M.C., Pini, E., Valenti, D., Schlich, M., Sinico, C., Marceddu, S., Dragi\u0107evi\u0107, N., and Fadda, A.M. (2023). Nanosuspension-Based Dissolvable Microneedle Arrays to Enhance Diclofenac Skin Delivery. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15092308"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/2\/158\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:36:00Z","timestamp":1759919760000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/2\/158"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,25]]},"references-count":31,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["ph18020158"],"URL":"https:\/\/doi.org\/10.3390\/ph18020158","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,25]]}}}