{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T22:38:25Z","timestamp":1787611105752,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PhD scholarship from SECIHTI"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Insulin therapy remains essential for the management of diabetes mellitus; however, conventional subcutaneous injection continues to impose significant physical, psychological, and behavioral barriers that negatively affect treatment adherence and metabolic outcomes. Injection-related pain, fear of needles, local tissue complications, and psychological insulin resistance contribute to delayed insulin initiation, inadequate dose titration, and suboptimal glycemic control worldwide. In response, alternative insulin delivery routes (including oral, pulmonary, nasal, and transdermal strategies) have been explored to reduce invasiveness and improve patient experience. Among these, transdermal insulin delivery has emerged as a particularly promising approach due to its potential to bypass gastrointestinal degradation, provide controlled absorption, and enhance patient acceptance. Recent advances in microneedle-based systems and needle-free jet injectors have enabled effective transdermal insulin administration by overcoming the skin barrier while minimizing pain and discomfort. This narrative review synthesizes current evidence on insulin delivery technologies with a specific focus on transdermal and needle-free systems. We discuss the biological and physicochemical challenges of insulin transport, the mechanisms underlying emerging delivery platforms, and clinical evidence regarding metabolic efficacy, glycemic variability, and patient-reported outcomes. The integration of these technologies with continuous glucose monitoring is also explored. Finally, we address translational challenges and future perspectives, highlighting the role of needle-free insulin delivery as a patient-centered strategy to improve adherence and metabolic control in diabetes care.<\/jats:p>","DOI":"10.3390\/life16030377","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T13:58:03Z","timestamp":1772114283000},"page":"377","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Advances in Insulin Delivery: Transdermal and Needle-Free Technologies as Emerging Strategies to Improve Metabolic Control and Treatment Adherence"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9216-0383","authenticated-orcid":false,"given":"Manuel","family":"Garc\u00eda-S\u00e1enz","sequence":"first","affiliation":[{"name":"Servicio de Endocrinolog\u00eda, Hospital de Especialidades del Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2503-8702","authenticated-orcid":false,"given":"Oscar Josu\u00e9","family":"G\u00f3mez-Romero","sequence":"additional","affiliation":[{"name":"Servicio de Endocrinolog\u00eda, Hospital de Especialidades del Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etual","family":"Espinosa-C\u00e1rdenas","sequence":"additional","affiliation":[{"name":"Servicio de Endocrinolog\u00eda, Hospital de Especialidades del Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3025-8339","authenticated-orcid":false,"given":"Claudia","family":"Ram\u00edrez-Renter\u00eda","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n M\u00e9dica en Enfermedades Endocrinas, Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1790-4408","authenticated-orcid":false,"given":"Jos\u00e9 Luis Eduardo","family":"Doval-Caballero","sequence":"additional","affiliation":[{"name":"Cl\u00ednica de Obesidad, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n \u201cSalvador Zubir\u00e1n\u201d, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Uribe-Cort\u00e9s","sequence":"additional","affiliation":[{"name":"Hospital \u00c1ngeles Cl\u00ednica Londres Torre Frontera, Mexico City 06700, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5159-9856","authenticated-orcid":false,"given":"Aldo","family":"Ferreira-Hermosillo","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n M\u00e9dica en Enfermedades Endocrinas, Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15019","DOI":"10.1038\/nrdp.2015.19","article-title":"Type 2 diabetes mellitus","volume":"1","author":"DeFronzo","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","first-page":"80","article-title":"The Cost-effectiveness of a Flash Glucose Monitoring System for Management of Patients with Type 2 Diabetes Receiving Intensive Insulin Treatment in Sweden","volume":"14","author":"Bilir","year":"2018","journal-title":"Eur. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee (2024). 6. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes\u20142024. Diabetes Care, 47, S111\u2013S125.","DOI":"10.2337\/dc24-S006"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee (2024). 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2024. Diabetes Care, 47, S158\u2013S178.","DOI":"10.2337\/dc24-S009"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wang, W., Men, L., Wang, Y., Shi, C., Yin, H., Li, H., Zhou, H., and Du, J. (2024). Effect of needle-free injection on psychological insulin resistance and insulin dosage in patients with type 2 diabetes. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1379830"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1007\/s13300-023-01468-4","article-title":"Insulin Therapy for the Management of Diabetes Mellitus: A Narrative Review of Innovative Treatment Strategies","volume":"14","author":"Nkonge","year":"2023","journal-title":"Diabetes Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e121","DOI":"10.1097\/MJT.0000000000001076","article-title":"Insulin Therapy: Future Perspectives","volume":"27","author":"Cernea","year":"2020","journal-title":"Am. J. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"102478","DOI":"10.1016\/j.dsx.2022.102478","article-title":"Non-invasive ways of administering insulin","volume":"16","author":"Capoccia","year":"2022","journal-title":"Diabetes Metab. Syndr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"109996","DOI":"10.1016\/j.diabres.2022.109996","article-title":"Transdermal drug delivery systems for the effective management of type 2 diabetes mellitus: A review","volume":"194","author":"Thirunavukkarasu","year":"2022","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"469","DOI":"10.7861\/clinmed.2020-0034","article-title":"Diabetes technologies\u2014What the general physician needs to know","volume":"20","author":"Li","year":"2020","journal-title":"Clin. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/s41586-025-09729-x","article-title":"A skin-permeable polymer for non-invasive transdermal insulin delivery","volume":"648","author":"Wei","year":"2025","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.jcis.2021.07.126","article-title":"On-demand transdermal insulin delivery system for type 1 diabetes therapy with no hypoglycemia risks","volume":"605","author":"Fu","year":"2022","journal-title":"J. Colloid Interface Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1039\/D5PM00091B","article-title":"Needle-free transdermal patches for insulin delivery in diabetes treatment","volume":"2","author":"Li","year":"2025","journal-title":"RSC Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.addr.2018.12.006","article-title":"Advances in transdermal insulin delivery","volume":"139","author":"Zhang","year":"2019","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1007\/s13346-021-01077-3","article-title":"Microneedle-based insulin transdermal delivery system: Current status and translation challenges","volume":"12","author":"Zhao","year":"2022","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"173","DOI":"10.30827\/ars.v64i2.27256","article-title":"Cuestionarios de adherencia al tratamiento antidiab\u00e9tico oral en pacientes con Diabetes Mellitus 2: Revisi\u00f3n sistem\u00e1tica","volume":"64","year":"2023","journal-title":"Ars Pharm."},{"key":"ref_17","first-page":"163","article-title":"M\u00e9todos para medir la adherencia terap\u00e9utica","volume":"59","year":"2018","journal-title":"Ars Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Prado-Aguilar, C.A., Martinez, Y.V., Segovia-Bernal, Y., Reyes-Martinez, R., and Arias-Ulloa, R. (2009). Performance of two questionnaires to measure treatment adherence in patients with Type-2 diabetes. BMC Public Health, 9.","DOI":"10.1186\/1471-2458-9-38"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"20503121231225319","DOI":"10.1177\/20503121231225319","article-title":"A review on oral novel delivery systems of insulin through the novel delivery system formulations: A review","volume":"12","author":"Limenh","year":"2024","journal-title":"SAGE Open Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1021\/acsbiomaterials.4c02000","article-title":"Transdermal Insulin Delivery Using Ionic Liquid-Mediated Nanovesicles for Diabetes Treatment","volume":"11","author":"Nabila","year":"2025","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1586\/17434440.3.5.565","article-title":"Needle-free liquid jet injections: Mechanisms and applications","volume":"3","author":"Baxter","year":"2006","journal-title":"Expert Rev. Med. Devices"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"130301","DOI":"10.1016\/j.ijbiomac.2024.130301","article-title":"Latest advances in glucose-responsive microneedle-based systems for transdermal insulin delivery","volume":"263","author":"Guillot","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1007\/s11095-011-0435-4","article-title":"Transdermal insulin delivery using microdermabrasion","volume":"28","author":"Andrews","year":"2011","journal-title":"Pharm. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1089\/152091502760306562","article-title":"Transdermal delivery of insulin from a novel biphasic lipid system in diabetic rats","volume":"4","author":"King","year":"2002","journal-title":"Diabetes Technol. Ther."},{"key":"ref_25","first-page":"16","article-title":"Recent Advances and Future Prospects of Non-Invasive Insulin Delivery Systems","volume":"11","author":"Mubara","year":"2019","journal-title":"Int. J. Appl. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1089\/dia.2011.0077","article-title":"Painless skin electroporation as a novel way for insulin delivery","volume":"13","author":"Wong","year":"2011","journal-title":"Diabetes Technol. Ther."},{"key":"ref_27","first-page":"335","article-title":"Dose comparison of ultrasonic transdermal insulin delivery to subcutaneous insulin injection","volume":"3","author":"Park","year":"2008","journal-title":"Int. J. Nanomed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1080\/17425247.2019.1649251","article-title":"Efficacy and safety of a needle-free injector in Chinese patients with type 2 diabetes mellitus treated with basal insulin: A multicentre, prospective, randomised, crossover study","volume":"16","author":"Xing","year":"2019","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.2337\/dc11-0182","article-title":"Improved pharmacokinetic and pharmacodynamic profile of rapid-acting insulin using needle-free jet injection technology","volume":"34","author":"Engwerda","year":"2011","journal-title":"Diabetes Care"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3436","DOI":"10.2337\/dc13-0492","article-title":"Needle-free jet injection of rapid-acting insulin improves early postprandial glucose control in patients with diabetes","volume":"36","author":"Engwerda","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"100368","DOI":"10.1016\/j.eclinm.2020.100368","article-title":"Insulin delivery with a needle-free insulin injector versus a conventional insulin pen in Chinese patients with type 2 diabetes mellitus: A 16-week, multicenter, randomized clinical trial (the FREE study)","volume":"23","author":"Ji","year":"2020","journal-title":"eClinicalMedicine"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1080\/17425247.2020.1738381","article-title":"Comparison of glucose variability in patients with type 2 diabetes administrated glargine with needle-free jet injector and conventional insulin pen","volume":"17","author":"Sun","year":"2020","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1080\/17425247.2022.2147504","article-title":"Needle-free injection of basal insulin improves fasting glucose variability as assessed by continuous glucose monitoring in T2DM: A prospective randomized multicenter open-label crossover study","volume":"19","author":"Sun","year":"2022","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1177\/1932296817699638","article-title":"Pharmacokinetic and Pharmacodynamic Variability of Insulin When Administered by Jet Injection","volume":"11","author":"Engwerda","year":"2017","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1111\/dom.12550","article-title":"Insulin administered by needle-free jet injection corrects marked hyperglycaemia faster in overweight or obese patients with diabetes","volume":"17","author":"Engwerda","year":"2015","journal-title":"Diabetes Obes. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pan, Q., Zhang, L., Gu, A., Yu, D., Wang, X., Zhou, Y., and Guo, L. (2022). The Absorption of Needle-Free Insulin Aspart Through Jet Injector in Different Body Parts of Healthy Individuals. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.832726"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e42389","DOI":"10.2196\/42389","article-title":"The Clinical Impact of Flash Glucose Monitoring-a Digital Health App and Smartwatch Technology in Patients With Type 2 Diabetes: Scoping Review","volume":"8","author":"Fellas","year":"2023","journal-title":"JMIR Diabetes"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"20","DOI":"10.17925\/EE.2022.18.1.20","article-title":"Utilizing the New Glucometrics: A Practical Guide to Ambulatory Glucose Profile Interpretation","volume":"18","author":"Doupis","year":"2022","journal-title":"touchREVIEWS Endocrinol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"S25","DOI":"10.1089\/dia.2017.0035","article-title":"Continuous Glucose Monitoring: A Review of Recent Studies Demonstrating Improved Glycemic Outcomes","volume":"19","author":"Rodbard","year":"2017","journal-title":"Diabetes Technol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1007\/s12325-019-00951-4","article-title":"Study Protocol for a Prospective, Multicenter, Randomized, Open-Label, Parallel-Group Clinical Trial Comparing the Efficacy and Safety of a Needle-Free Insulin Injector and a Conventional Insulin Pen in Controlling Blood Glucose Concentrations in Chinese Patients with Type 2 Diabetes Mellitus (The FREE Study)","volume":"36","author":"Ji","year":"2019","journal-title":"Adv. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s40271-015-0160-x","article-title":"A Systematic Review of Patients\u2019 Perspectives on the Subcutaneous Route of Medication Administration","volume":"9","author":"Ridyard","year":"2016","journal-title":"Patient"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1177\/19322968211053895","article-title":"Jet-Induced Blood Release From Human Fingertips: A Single-Blind, Randomized, Crossover Trial","volume":"17","author":"Xu","year":"2023","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_43","unstructured":"Palylyk-Colwell, E., and Ford, C. (2016). Flash Glucose Monitoring System for Diabetes. CADTH Issues in Emerging Health Technologies, CADTH. CADTH Horizon Scans."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1089\/dia.2017.0021","article-title":"How Can We Realize the Clinical Benefits of Continuous Glucose Monitoring?","volume":"19","author":"Ajjan","year":"2017","journal-title":"Diabetes Technol. Ther."},{"key":"ref_45","unstructured":"Bidonde, J., Fagerlund, B.C., Fronsdal, K.B., Lund, U.H., and Robberstad, B. (2017). FreeStyle Libre Flash Glucose Self-Monitoring System: A Single-Technology Assessment, NIPH. NIPH Systematic Reviews."},{"key":"ref_46","unstructured":"American Diabetes Association (2018). Role of Continuous Glucose Monitoring in Diabetes Treatment, American Diabetes Association."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.jdiacomp.2018.10.012","article-title":"Freestyle Libre trend arrows for the management of adults with insulin-treated diabetes: A practical approach","volume":"33","author":"Bianchi","year":"2019","journal-title":"J. Diabetes Complicat."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee (2024). 7. Diabetes Technology: Standards of Care in Diabetes-2024. Diabetes Care, 47, S126\u2013S144.","DOI":"10.2337\/dc24-S007"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1177\/1932296818822496","article-title":"The Relationships Between Time in Range, Hyperglycemia Metrics, and HbA1c","volume":"13","author":"Beck","year":"2019","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1089\/dia.2018.0310","article-title":"The Relationship of Hemoglobin A1C to Time-in-Range in Patients with Diabetes","volume":"21","author":"Vigersky","year":"2019","journal-title":"Diabetes Technol. Ther."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/3\/377\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T14:15:53Z","timestamp":1772115353000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/3\/377"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,26]]},"references-count":50,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["life16030377"],"URL":"https:\/\/doi.org\/10.3390\/life16030377","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,26]]}}}