{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T08:04:24Z","timestamp":1778227464182,"version":"3.51.4"},"reference-count":21,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T00:00:00Z","timestamp":1752105600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institute of Health Research","doi-asserted-by":"crossref","award":["Grant - 264437"],"award-info":[{"award-number":["Grant - 264437"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Fonds du Recherche du Quebec","award":["324852"],"award-info":[{"award-number":["324852"]}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institute of Health Research","doi-asserted-by":"crossref","award":["FBD-181455"],"award-info":[{"award-number":["FBD-181455"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Salivary Glands (SGs) are vital organs that are particularly prone to damage due to head and neck cancer radiation treatment, as well as other autoimmune disorders. SG hypofunction often impairs the production of saliva, which causes a significant loss of functioning for the oral cavity. There are a multitude of treatments for rescuing SG hypofunction; however, they are usually administered systemically, causing adverse effects and requiring higher doses of the agents. More localised approaches have demonstrated adequate potential as alternative treatments but are still in their initial stages of investigation. This study proposes a localised delivery technique termed as the \u2018Intraglandular (IG) Non-Surgical Transcutaneous Injection,\u2019 to deliver cell and cell-free therapies into the submandibular salivary glands (SMGs) of mice. First, we used anatomical landmarks, radiography, and tissue dissection to devise a method to localise the center of the SMGs with either a pen marker or a customized plastic stent. Second, we used a dye (trypan blue) to verify the accuracy of the injection technique to the SMGs. Third, we injected Green Fluorescent Protein Bone Marrow Mesenchymal Stem Cells (GFP\u2009+\u2009ve BM-MSC) and tracked them for 7 days in SMGs to further demonstrate that the cells were embedded into SMG tissue and that our injection technique did not injure the glandular morphology. We therefore hypothesize that this IG technique would provide a less invasive, lower dose and highly accurate administration of cell and cell-free therapies to hypofunctional mice SMGs.<\/jats:p>","DOI":"10.1371\/journal.pone.0326769","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T17:49:18Z","timestamp":1752169758000},"page":"e0326769","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Using a non-surgical transcutaneous intraglandular injection technique to deliver cell and cell-free therapies to murine submandibular salivary glands"],"prefix":"10.1371","volume":"20","author":[{"given":"Arvind","family":"Hariharan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janaki","family":"Iyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akram","family":"Almansoori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Younan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meet","family":"Shah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9875-2600","authenticated-orcid":true,"given":"Piotr","family":"Pater","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5363-3124","authenticated-orcid":true,"given":"Tyler","family":"Lalonde","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5594-359X","authenticated-orcid":true,"given":"Simon D.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,7,10]]},"reference":[{"issue":"1","key":"pone.0326769.ref001","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.cden.2019.08.007","article-title":"Salivary Gland Diseases","volume":"64","author":"OE Ogle","year":"2020","journal-title":"Dent Clin North Am"},{"issue":"3","key":"pone.0326769.ref002","doi-asserted-by":"crossref","first-page":"541","DOI":"10.3390\/ijms20030541","article-title":"Localized Delivery of Pilocarpine to Hypofunctional Salivary Glands through Electrospun Nanofiber Mats: An Ex Vivo and In Vivo Study","volume":"20","author":"S Muthumariappan","year":"2019","journal-title":"Int J Mol Sci"},{"key":"pone.0326769.ref003","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/5584_2023_765","article-title":"Drug therapeutics delivery to the salivary glands: intraglandular and intraductal injections.","volume-title":"Cell biology and translational medicine, volume 20: organ function, maintenance, repair in health and disease","author":"AA Almansoori","year":"2023"},{"key":"pone.0326769.ref004","first-page":"39","article-title":"Mesenchymal Stem Cell Exosomes: The Future MSC-Based Therapy?","volume-title":"Mesenchymal Stem Cell Therapy","author":"RC Lai","year":"2013"},{"issue":"11","key":"pone.0326769.ref005","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1177\/0022034518767408","article-title":"Localized delivery of amifostine enhances salivary gland radioprotection","volume":"97","author":"JJ Varghese","year":"2018","journal-title":"J Dent Res"},{"key":"pone.0326769.ref006","first-page":"101385","article-title":"A novel cell-based transplantation method using a Rho kinase inhibitor and a specific catheter device for the treatment of salivary gland damage after head and neck radiotherapy","volume":"32","author":"A Kasamatsu","year":"2022","journal-title":"Biochem Biophys Rep"},{"issue":"5","key":"pone.0326769.ref007","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1002\/lio2.306","article-title":"Intraductal Salivary Gland Infusion With Botulinum Toxin","volume":"4","author":"AT Schwalje","year":"2019","journal-title":"Laryngoscope Investig Otolaryngol"},{"issue":"135","key":"pone.0326769.ref008","doi-asserted-by":"crossref","DOI":"10.3791\/57521","article-title":"Retroductal Nanoparticle Injection to the Murine Submandibular Gland","author":"JJ Varghese","year":"2018","journal-title":"J Vis Exp"},{"issue":"7","key":"pone.0326769.ref009","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.3390\/pharmaceutics15071844","article-title":"Localized drug delivery systems: An update on treatment options for head and neck squamous cell carcinomas","volume":"15","author":"A Hariharan","year":"2023","journal-title":"Pharmaceutics"},{"issue":"2","key":"pone.0326769.ref010","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.jconrel.2011.01.027","article-title":"Advances in oral transmucosal drug delivery","volume":"153","author":"VF Patel","year":"2011","journal-title":"J Control Release"},{"issue":"7","key":"pone.0326769.ref011","doi-asserted-by":"crossref","DOI":"10.1038\/bdj.2007.80","article-title":"A controlled release pilocarpine buccal insert in the treatment of Sj\u00f6gren\u2019s syndrome","volume":"202","author":"J Gibson","year":"2007","journal-title":"Br Dent J"},{"issue":"7","key":"pone.0326769.ref012","doi-asserted-by":"crossref","first-page":"302","DOI":"10.3390\/pharmaceutics11070302","article-title":"Controlled Drug Delivery Systems for Oral Cancer Treatment-Current Status and Future Perspectives","volume":"11","author":"F Ketabat","year":"2019","journal-title":"Pharmaceutics"},{"issue":"1","key":"pone.0326769.ref013","doi-asserted-by":"crossref","first-page":"64","DOI":"10.3390\/toxins14010064","article-title":"Safety of High-Dose Botulinum Toxin Injections for Parotid and Submandibular Gland Radioprotection","volume":"14","author":"J Mueller","year":"2022","journal-title":"Toxins (Basel)"},{"issue":"26","key":"pone.0326769.ref014","doi-asserted-by":"crossref","DOI":"10.1097\/MD.0000000000020788","article-title":"Phase 1 clinical study of cell therapy with effective-mononuclear cells (E-MNC) for radiogenic xerostomia (first-in-human study) (FIH study on E-MNC therapy for radiogenic xerostomia)","volume":"99","author":"Y Sumita","year":"2020","journal-title":"Medicine (Baltimore)"},{"issue":"4","key":"pone.0326769.ref015","article-title":"Paracrine effects of bone marrow soup restore organ function, regeneration, and repair in salivary glands damaged by irradiation","volume":"8","author":"SD Tran","year":"2013","journal-title":"PLoS One"},{"issue":"4","key":"pone.0326769.ref016","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/S0306-9877(97)90103-1","article-title":"Sialorrhea in amyotrophic lateral sclerosis: a hypothesis of a new treatment--botulinum toxin A injections of the parotid glands","volume":"48","author":"KO Bushara","year":"1997","journal-title":"Med Hypotheses"},{"issue":"5","key":"pone.0326769.ref017","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.3390\/toxins5051010","article-title":"Sialorrhea: anatomy, pathophysiology and treatment with emphasis on the role of botulinum toxins","volume":"5","author":"AA Lakraj","year":"2013","journal-title":"Toxins (Basel)"},{"issue":"15","key":"pone.0326769.ref018","doi-asserted-by":"crossref","first-page":"3910","DOI":"10.3390\/cancers13153910","article-title":"An Overview on the Histogenesis and Morphogenesis of Salivary Gland Neoplasms and Evolving Diagnostic Approaches","volume":"13","author":"J Iyer","year":"2021","journal-title":"Cancers (Basel)"},{"issue":"1","key":"pone.0326769.ref019","doi-asserted-by":"crossref","first-page":"51","DOI":"10.5535\/arm.2017.41.1.51","article-title":"Accuracy of Ultrasound-Guided and Non-ultrasound-Guided Botulinum Toxin Injection Into Cadaver Salivary Glands","volume":"41","author":"JI So","year":"2017","journal-title":"Ann Rehabil Med"},{"issue":"1","key":"pone.0326769.ref020","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/s43856-022-00223-3","article-title":"Intraglandular mesenchymal stem cell treatment induces changes in the salivary proteome of irradiated patients","volume":"2","author":"CD Lynggaard","year":"2022","journal-title":"Commun Med (Lond)"},{"issue":"3","key":"pone.0326769.ref021","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1177\/0022034519898138","article-title":"Labial Stem Cell Extract Mitigates Injury to Irradiated Salivary Glands","volume":"99","author":"X Su","year":"2020","journal-title":"J Dent Res"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0326769","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T17:49:26Z","timestamp":1752169766000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0326769"}},"subtitle":[],"editor":[{"given":"Giovanni","family":"Di Pasquale","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,7,10]]},"references-count":21,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0326769","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,10]]}}}