{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T21:10:44Z","timestamp":1783717844042,"version":"3.55.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The aim of this study is to determine the most effective physical parameters for optimizing the transdermal delivery of lidocaine cream.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Preliminary experiments were conducted to optimize ultrasound settings while ensuring safety, guided by visual and histopathological evaluations following observations of skin burns in rats. <jats:italic>Ex vivo<\/jats:italic> assessments of lidocaine penetration into isolated porcine ear tissue were conducted using Franz diffusion cells and confocal laser scanning microscopy under different intervention conditions <jats:italic>In vivo<\/jats:italic> analysis involved measuring lidocaine concentrations in rat skin following treatments combining ultrasound and microneedle rollers. The anesthetic efficacy of these interventions was further assessed using the \u201crat tail-flick test.\u201d<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Twelve non-invasive parameter configurations involving ultrasound and microneedle rollers were identified. The combination of ultrasound and microneedle rollers yielded superior results while the ultrasound-only groups demonstrated improved diffusion compared to the control. Notably, ultrasound applied at 260\u00a0kHz with a 90% duty cycle, in conjunction with microneedle rollers, achieved the highest diffusion rates, with <jats:italic>ex vivo<\/jats:italic> cumulative lidocaine permeation at 15\u00a0min reaching 45.81 \u00b1 4.19\u00a0\u03bcg\/cm<jats:sup>2<\/jats:sup> (vs. baseline 60\u00a0min value, p = 0.0017) and microneedle roller alone at 48.62 \u00b1 6.73\u00a0\u03bcg\/cm<jats:sup>2<\/jats:sup> (p &amp;lt; 0.0001). Confocal laser scanning microscopy demonstrated minimal lidocaine penetration without interventions, whereas the combined ultrasound and microneedle approach resulted in significantly enhanced penetration, with visible fluorescence deep in the dermis within 5\u00a0min. <jats:italic>In vivo<\/jats:italic> findings corroborated these results, with the combined method facilitating the most rapid onset of anesthesia (mean onset time 28.75 \u00b1 6.41\u00a0min, p &amp;lt; 0.05 vs control 67.50 \u00b1 4.63\u00a0min) and improved transdermal delivery compared to other groups, achieving 100% anesthetic efficiency rate at 60\u00a0min vs. 25% in control.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Microneedle rollers demonstrate superior clinical efficacy over ultrasound, enabling rapid lidocaine delivery (15-min onset <jats:italic>ex vivo<\/jats:italic>; 32.5-min anesthesia <jats:italic>in vivo<\/jats:italic>) and achieving 100% anesthetic efficiency for time-sensitive procedures\u2014establishing a practical paradigm shift in transdermal local anesthesia.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fbioe.2025.1612145","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T05:38:02Z","timestamp":1752644282000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Enhanced transdermal delivery of lidocaine cream via ultrasound and microneedle rollers"],"prefix":"10.3389","volume":"13","author":[{"given":"Jiaxiao","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanjuan","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wensheng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqin","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1962","DOI":"10.1007\/s13346-024-01722-7","article-title":"Iontophoresis and electroporation-assisted microneedles: advancements and therapeutic potentials in transdermal drug delivery","volume":"15","author":"Abbasi","year":"2024","journal-title":"Drug Deliv. Transl. Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/1061186X.2024.2447793","article-title":"Nanotransethosomal dual-drug loaded gel of methotrexate and mangiferin as a potent synergistic intervention for rheumatoid arthritis via transdermal delivery","author":"Adin","year":"2024","journal-title":"J. drug Target."},{"key":"B3","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.pbiomolbio.2012.01.004","article-title":"Bio-effects and safety of low-intensity, low-frequency ultrasonic exposure","volume":"108","author":"Ahmadi","year":"2012","journal-title":"Prog. Biophysics Mol. Biol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/s10840-018-0473-5","article-title":"High-power, low-flow, short-ablation duration-the key to avoid collateral injury?","volume":"55","author":"Ali-Ahmed","year":"2018","journal-title":"J. interventional cardiac Electrophysiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.ejpb.2004.03.027","article-title":"Visualization of skin penetration using confocal laser scanning microscopy","volume":"58","author":"Alvarez-Rom\u00e1n","year":"2004","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1080\/17425247.2016.1192123","article-title":"The progressive role of Acoustic cavitation for non-invasive therapies, contrast imaging and blood-tumor permeability enhancement","volume":"13","author":"Aw","year":"2016","journal-title":"Expert Opin. Drug Deliv."},{"key":"B7","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.addr.2014.01.007","article-title":"Ultrasound mediated transdermal drug delivery","volume":"72","author":"Azagury","year":"2014","journal-title":"Adv. drug Deliv. Rev."},{"key":"B8","doi-asserted-by":"publisher","first-page":"3858","DOI":"10.1038\/s41467-021-23736-2","article-title":"Site selective C\u2013H functionalization of mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy","volume":"12","author":"Bhowmik","year":"2021","journal-title":"Nat. Commun."},{"key":"B9","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/s0168-3659(02)00054-8","article-title":"Effect of sonication parameters on transdermal delivery of insulin to hairless rats","volume":"81","author":"Boucaud","year":"2002","journal-title":"J. Control. release"},{"key":"B10","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/s0378-5173(01)00820-1","article-title":"In vitro study of low-frequency ultrasound-enhanced transdermal transport of fentanyl and caffeine across human and hairless rat skin","volume":"228","author":"Boucaud","year":"2001","journal-title":"Int. J. Pharm."},{"key":"B11","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1093\/ptj\/83.8.707","article-title":"Phonophoresis versus topical application of ketoprofen: Comparison between tissue and plasma levels","volume":"83","author":"Cagnie","year":"2003","journal-title":"Phys. Ther."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e20220008","DOI":"10.1590\/1980-220x-reeusp-2022-0008en","article-title":"Pain management in hospitalized children: a cross-sectional study","volume":"56","author":"Carvalho","year":"2022","journal-title":"Rev. Esc. Enferm. USP"},{"key":"B13","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.snb.2009.11.013","article-title":"Sonophoretic enhanced microneedles array (SEMA)\u2014Improving the efficiency of transdermal drug delivery","volume":"145","author":"Chen","year":"2010","journal-title":"Sensors Actuators B Chem."},{"key":"B14","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1177\/00099228231196473","article-title":"Pain prevalence and treatment in hospitalized children and adolescents at a US tertiary pediatric hospital","volume":"63","author":"De Souza","year":"2023","journal-title":"Clin. Pediatr."},{"key":"B15","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/s0022-3565(25)08751-8","article-title":"Methods for the study of irritation and toxicity of substances applied topically to the skin and the mucous membranes","volume":"82","author":"Draize","year":"1944","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1016\/j.addr.2008.03.007","article-title":"Ultrasound mediated delivery of drugs and genes to solid tumors","volume":"60","author":"Frenkel","year":"2008","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3614","DOI":"10.1002\/jps.23662","article-title":"Permeability enhancement for transdermal delivery of large molecule using low-frequency sonophoresis combined with microneedles","volume":"102","author":"Han","year":"2013","journal-title":"J. Pharm. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.ejpb.2014.12.020","article-title":"Potential of combined ultrasound and microneedles for enhanced transdermal drug permeation: a review","volume":"89","author":"Han","year":"2014","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"B19","doi-asserted-by":"publisher","first-page":"105942","DOI":"10.1016\/j.ultsonch.2022.105942","article-title":"Improvement of gelation properties of silver carp surimi through ultrasound-assisted water Bath heating","volume":"83","author":"He","year":"2022","journal-title":"Ultrason. sonochemistry"},{"key":"B20","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s40824-021-00226-6","article-title":"Recent advances in transdermal drug delivery systems: a review","volume":"25","author":"Jeong","year":"2021","journal-title":"Biomaterials Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1758","DOI":"10.3390\/pharmaceutics14091758","article-title":"Sugar-triggered burst drug releasing poly-lactic acid (PLA) microneedles and its fabrication based on solvent-casting approach","volume":"14","author":"Kang","year":"2022","journal-title":"Pharmaceutics"},{"key":"B22","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.ejpb.2021.09.003","article-title":"Influence of mechanical skin treatment (massage, ultrasound, microdermabrasion, tape stripping and microneedling) on dermal penetration efficacy of chemical compounds","volume":"169","author":"Kaushik","year":"2021","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"B23","first-page":"1","article-title":"Anesthetic effects of lidocaine hydrochloride gel using low frequency ultrasound of 0.5 MHz","volume":"10","author":"Kim","year":"2007","journal-title":"J. Pharm. and Pharm. Sci."},{"key":"B24","volume-title":"Ultrasound as a transdermal enhancer [Z]","author":"Kost","year":"1989"},{"key":"B25","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1021\/cn500256e","article-title":"Brain tissue responses to neural implants impact signal sensitivity and intervention strategies","volume":"6","author":"Kozai","year":"2015","journal-title":"ACS Chem. Neurosci."},{"key":"B26","first-page":"99","article-title":"Principles of office anesthesia: part II. Topical anesthesia","volume":"66","author":"Kundu","year":"2002","journal-title":"Am. Fam. Physician"},{"key":"B27","doi-asserted-by":"publisher","first-page":"211","DOI":"10.3390\/pharmaceutics10040211","article-title":"Universal applicator for digitally-controlled pressing force and impact velocity insertion of microneedles into skin","volume":"10","author":"Leone","year":"2018","journal-title":"Pharmaceutics"},{"key":"B28","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.ijpharm.2006.07.022","article-title":"Investigation into the potential of low-frequency ultrasound facilitated topical delivery of cyclosporin A","volume":"326","author":"Liu","year":"2006","journal-title":"Int. J. Pharm."},{"key":"B29","doi-asserted-by":"publisher","first-page":"21501327211007393","DOI":"10.1177\/21501327211007393","article-title":"Considering needle phobia among adult patients during mass COVID-19 vaccinations","volume":"12","author":"Love","year":"2021","journal-title":"J. Prim. Care and Community Health"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0378-5173(02)00299-5","article-title":"Phonophoresis: efficiency, mechanisms and skin tolerance","volume":"243","author":"Machet","year":"2002","journal-title":"Int. J. Pharm."},{"key":"B31","doi-asserted-by":"publisher","first-page":"564","DOI":"10.3109\/10717544.2014.935532","article-title":"Permeation enhancer strategies in transdermal drug delivery","volume":"23","author":"Marwah","year":"2014","journal-title":"Drug Deliv."},{"key":"B32","doi-asserted-by":"publisher","first-page":"623","DOI":"10.7863\/jum.2012.31.4.623","article-title":"Overview of therapeutic ultrasound applications and safety considerations","volume":"31","author":"Miller","year":"2012","journal-title":"J. Ultrasound Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/s0168-3659(03)00306-7","article-title":"Characterization of transdermal solute transport induced by low-frequency ultrasound in the hairless rat skin","volume":"92","author":"Mutoh","year":"2003","journal-title":"J. Control. Release"},{"key":"B34","doi-asserted-by":"publisher","first-page":"15593258221097594","DOI":"10.1177\/15593258221097594","article-title":"Feasibility of enhancing skin permeability of acyclovir through sterile topical lyophilized wafer on self-dissolving microneedle-treated skin","volume":"20","author":"Nagra","year":"2022","journal-title":"Dose-Response"},{"key":"B35","doi-asserted-by":"publisher","first-page":"658","DOI":"10.3109\/10717544.2014.935985","article-title":"Lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel delivery by combined microneedle and ultrasound","volume":"23","author":"Nayak","year":"2014","journal-title":"Drug Deliv."},{"key":"B36","doi-asserted-by":"publisher","first-page":"855","DOI":"10.3390\/pharmaceutics12090855","article-title":"Transfersomes: a promising nanoencapsulation technique for transdermal drug delivery","volume":"12","author":"Opatha","year":"2020","journal-title":"Pharmaceutics"},{"key":"B37","doi-asserted-by":"publisher","first-page":"56","DOI":"10.2174\/1874120701004010056","article-title":"Transdermal drug delivery aided by an ultrasound contrast agent: an in vitro experimental study","volume":"4","author":"Park","year":"2010","journal-title":"Open Biomed. Eng. J."},{"key":"B38","doi-asserted-by":"publisher","first-page":"44236","DOI":"10.1038\/srep44236","article-title":"Hydrogel increases localized transport regions and skin permeability during low frequency ultrasound treatment","volume":"7","author":"Pereira","year":"2017","journal-title":"Sci. Rep."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1248\/bpb.b14-00321","article-title":"The combination of microneedles with electroporation and sonophoresis to enhance hydrophilic macromolecule skin penetration","volume":"37","author":"Petchsangsai","year":"2014","journal-title":"Biol. Pharm. Bull."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1002\/cne.23461","article-title":"Organization of sensory input to the nociceptive-specific cutaneous trunk muscle reflex in rat, an effective experimental system for examining nociception and plasticity","volume":"522","author":"Petruska","year":"2014","journal-title":"J. Comp. Neurology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.jconrel.2022.09.025","article-title":"Overcoming skin barriers through advanced transdermal drug delivery approaches","volume":"351","author":"Phatale","year":"2022","journal-title":"J. Control. release"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1517\/17425247.2010.538679","article-title":"Low-frequency sonophoresis: application to the transdermal delivery of macromolecules and hydrophilic drugs","volume":"7","author":"Polat","year":"2010","journal-title":"Expert Opin. Drug Deliv."},{"key":"B43","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.jconrel.2011.01.006","article-title":"Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends","volume":"152","author":"Polat","year":"2011","journal-title":"J. Control. Release"},{"key":"B44","doi-asserted-by":"publisher","first-page":"7749","DOI":"10.2147\/ijn.s174759","article-title":"Recent advances in ultrasound-based transdermal drug delivery","volume":"13","author":"Seah","year":"2018","journal-title":"Int. J. Nanomedicine"},{"key":"B45","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1080\/01926230252824761","article-title":"Qualitative and quantitative analysis of nonneoplastic lesions in toxicology studies","volume":"30","author":"Shackelford","year":"2002","journal-title":"Toxicol. Pathol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"eabq3104","DOI":"10.1126\/sciadv.abq3104","article-title":"Eyedrop-based macromolecular ophthalmic drug delivery for ocular fundus disease treatment","volume":"9","author":"Shen","year":"2023","journal-title":"Sci. Adv."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1081\/ddc-100100984","article-title":"Permeation enhancers for transdermal drug delivery","volume":"26","author":"Sinha","year":"2000","journal-title":"Drug Dev. industrial Pharm."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2557","DOI":"10.3390\/nano11102557","article-title":"Ultraflexible liposome nanocargo as a dermal and transdermal drug delivery system","volume":"11","author":"Sudhakar","year":"2021","journal-title":"Nanomaterials"},{"key":"B49","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1111\/srt.12968","article-title":"Methods for evaluating penetration of drug into the skin: a review","volume":"27","author":"Supe","year":"2020","journal-title":"Skin Res. Technol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"E227","DOI":"10.1503\/cmaj.160542","article-title":"Relative effectiveness of additive pain interventions during vaccination in infants","volume":"189","author":"Taddio","year":"2016","journal-title":"Can. Med. Assoc. J."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1023\/a:1019898109793","article-title":"An investigation of the role of cavitation in low-frequency ultrasound-mediated transdermal drug transport","volume":"19","author":"Tang","year":"2002","journal-title":"Pharm. Res."},{"key":"B52","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1002\/jps.10000","article-title":"Synergistic effect of low\u2010frequency ultrasound and surfactants on skin permeability","volume":"91","author":"Tezel","year":"2002","journal-title":"J. Pharm. Sci."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1021\/acschemneuro.5b00137","article-title":"Synthesis of carfentanil amide opioids using the ugi multicomponent reaction","volume":"6","author":"V\u00e1radi","year":"2015","journal-title":"ACS Chem. Neurosci."},{"key":"B54","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1016\/j.ijpharm.2012.10.019","article-title":"Preparation and evaluation of lidocaine hydrochloride-loaded TAT-Conjugated polymeric liposomes for transdermal delivery","volume":"441","author":"Wang","year":"2013","journal-title":"Int. J. Pharm."},{"key":"B55","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1002\/9781118140505.ch18","article-title":"Transdermal and topical drug delivery today","author":"Watkinson","year":"2011","journal-title":"Top. Transdermal Drug Deliv."},{"key":"B56","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.jpba.2017.07.028","article-title":"LC\u2013MS\/MS method for preclinical pharmacokinetic study of QX-OH, a novel long-acting local anesthetic, in sciatic nerve blockade in rats","volume":"146","author":"Zhang","year":"2017","journal-title":"J. Pharm. Biomed. Analysis"},{"key":"B57","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.ijpharm.2015.05.035","article-title":"Ultrasound and electric pulses for transdermal drug delivery enhancement: ex vivo assessment of methods with in vivo oriented experimental protocols","volume":"490","author":"Zorec","year":"2015","journal-title":"Int. J. Pharm."}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2025.1612145\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T05:38:03Z","timestamp":1752644283000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2025.1612145\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,16]]},"references-count":57,"alternative-id":["10.3389\/fbioe.2025.1612145"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2025.1612145","relation":{},"ISSN":["2296-4185"],"issn-type":[{"value":"2296-4185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,16]]},"article-number":"1612145"}}