{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T17:46:58Z","timestamp":1790444818243,"version":"4.1.0"},"reference-count":116,"publisher":"Wiley","issue":"S277","license":[{"start":{"date-parts":[[2023,10,15]],"date-time":"2023-10-15T00:00:00Z","timestamp":1697328000000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Ophthalmologica"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>ENGLISH SUMMARY<\/jats:title><jats:p>Dry eye disease (DED) is characterized by ocular dryness, irritation and blurred vision and has a significant impact on the patient's quality of life. This condition can be particularly severe in patients with aqueous deficient dry eye disease (ADDE) due to Sj\u00f6gren's syndrome (SS), an autoimmune disease that affects the lacrimal and salivary glands. Current treatments for ADDE are often limited to symptomatic relief. A literature review was conducted to explore the current surgical interventions used or tested in humans with ADDE (I). These interventions include procedures involving the eyelids and tear ducts, transplantation of amniotic membrane or salivary glands, injections around the tear ducts and cell\u2010based injections into the lacrimal gland (LG). Each treatment has its advantages and disadvantages; however, treating dry eyes in patients with SS presents a particular challenge due to the systemic nature of the disease. Moreover, there is a need for new therapeutic options. Mesenchymal stem cells (MSCs) are a type of stem cell that have shown promise in regenerating damaged tissue and reducing inflammation in various diseases. Previous studies in animal models have suggested that MSCs could be effective in treating ADDE. Thus, this thesis aims to investigate the safety and efficacy of injecting MSCs into the LG as a treatment option for patients with ADDE secondary to SS. The study also aims to see this treatment in light of existing and novel investigational treatment options. The clinical studies conducted for this thesis are the first of their kind in humans. MSCs derived from healthy donors' adipose tissue (ASCs) were cultured in a laboratory, frozen and thawed ready for use. In the safety study, we performed the first human trial involving the administration of a single injection of ASCs into the LG of one eye in seven patients suffering from severe ADDE (II). The primary objective was to test the safety of this treatment, while the secondary objective was to assess improvements in subjective and objective signs of dry eye. The results of the trial showed no serious side effects within 4\u2009months of follow\u2010up after treatment. On average, there was a 40% reduction in dry eye symptoms assessed with the Ocular Surface Disease Index (OSDI) questionnaire. Additionally, in the treated eye, there was a significant decrease in tear osmolarity, an increase in tear film stability and an increase in tear production. To further investigate the efficacy of this treatment, our research group performed a clinical, randomized study aiming to compare the ASC injection into the LG with the injection of a vehicle (the excipient in which the ASCs are dissolved) and observation (no intervention) (III). The study involved 20 subjects receiving ASC injection, 20 subjects receiving vehicle injection and 14 patients being observed without intervention. The subjects were examined to assess the outcomes with a 12\u2010month follow\u2010up after treatment. Both intervention groups showed a significant reduction in subjective dry eye symptoms of approximately 40%. This improvement was evident at the 1\u2010week follow\u2010up and persisted until the 12\u2010month follow\u2010up. The observation group did not experience any change in OSDI score. The ASCs group exhibited a significant mean increase in non\u2010invasive tear break\u2010up time (NIKBUT) of 6.48\u2009s (149%) at the four\u2010week follow\u2010up, which was significantly higher than that in the vehicle group (<jats:italic>p<\/jats:italic>\u2009=\u20090.04). Moreover, the ASCs group showed a significant increase in NIKBUT compared to that in the observation group at the 12\u2010month follow\u2010up (<jats:italic>p<\/jats:italic>\u2009=\u20090.004). In both the ASCs and vehicle group, a significant increase in Schirmer test scores at the 4\u2010month follow\u2010up and the 12\u2010month follow\u2010up was observed. In conclusion, this thesis contributes valuable findings with a new treatment option for patients with dry eye disease. Injection of ASCs into the LG was shown to be safe and to improve subjective dry eye symptoms and specifically the tear film stability in patients with ADDE due to SS. Compared to other treatment modalities of ADDE, this treatment has greater potential, as ASCs could potentially be used as an anti\u2010inflammatory therapeutic option for managing DED of other causes as well.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESUM\u00c9 (DANISH SUMMARY)<\/jats:title><jats:p>T\u00f8rre \u00f8jne, karakteriseret ved t\u00f8rhedsfornemmelse og irritation af \u00f8jnene samt sl\u00f8ret syn, har en betydelig indvirkning p\u00e5 patientens livskvalitet. Denne tilstand kan v\u00e6re s\u00e6rligt alvorlig hos patienter med nedsat t\u00e5reproduktion (ADDE) som f\u00f8lge af Sj\u00f6grens syndrom (SS), en autoimmun sygdom, der p\u00e5virker t\u00e5rekirtlerne og spytkirtlerne. Nuv\u00e6rende behandlinger for ADDE er ofte begr\u00e6nset til symptomlindring. Vi gennemf\u00f8rte en litteraturgennemgang for at unders\u00f8ge, hvilke nuv\u00e6rende kirurgiske behandlingsmetoder, der anvendes eller testes hos patienter med ADDE (I). Disse interventioner inkluderer procedurer, der involverer \u00f8jenl\u00e5g og t\u00e5rekanaler, transplantation af amnionhinde eller spytkirtler, injektioner omkring t\u00e5rekanalerne samt cellebaserede injektioner i t\u00e5rekirtlen. Hver behandling har sine fordele og ulemper, men behandling af t\u00f8rre \u00f8jne hos patienter med SS udg\u00f8r en s\u00e6rlig udfordring p\u00e5 grund af sygdommens systemiske udbredning, og der er behov for nye behandlingsmuligheder. Mesenkymale stamceller (MSCs) er en type stamcelle, der har vist lovende resultater med hensyn til at regenerere beskadiget v\u00e6v og reducere inflammation i forskellige sygdomme. Tidligere unders\u00f8gelser i dyremodeller har indikeret, at MSCs kan v\u00e6re en effektiv behandling af ADDE. Denne afhandling har til form\u00e5l at unders\u00f8ge sikkerheden og effekten af injektion af MSCs i t\u00e5rekirtlen som en mulig behandling til patienter med ADDE som f\u00f8lge af SS. Afhandlingen sigter ogs\u00e5 mod at sammenligne denne behandling med andre eksisterende, kirurgiske behandlingsmuligheder af ADDE. Som led i dette projekt udf\u00f8rte vi de f\u00f8rste kliniske fors\u00f8g af sin art i mennesker. MSCs fra raske donorers fedtv\u00e6v (ASCs) blev dyrket i et laboratorium, frosset ned og er opt\u00f8et klar til brug. Det f\u00f8rste m\u00e5l var at teste sikkerheden ved denne behandling og sekund\u00e6rt at unders\u00f8ge behandlingens effekt. For at unders\u00f8ge dette modtog syv fors\u00f8gspersoner med sv\u00e6r ADDE \u00e9n injektion med ASCs i t\u00e5rekirtlen p\u00e5 det ene \u00f8je (II). Resultaterne af fors\u00f8get viste ingen alvorlige bivirkninger inden for fire m\u00e5neders opf\u00f8lgning efter behandlingen. I gennemsnit fandt vi yderligere en 40% reduktion i symptomer p\u00e5 t\u00f8rre \u00f8jne vurderet med et sp\u00f8rgeskema, og en markant stigning i t\u00e5reproduktionen og af t\u00e5refilmens stabilitet i det behandlede \u00f8je. For yderligere at unders\u00f8ge effekten af denne behandling udf\u00f8rte vi et klinisk, randomiseret fors\u00f8g med det form\u00e5l at sammenligne injektion af ASCs i t\u00e5rekirtlen med injektion af en kontrolopl\u00f8sning (v\u00e6sken, hvor stamcellerne var opl\u00f8st) og observation (ingen intervention) (III). Studiet omfattede 20 fors\u00f8gspersoner, der modtog ASC\u2010injektion, 20 fors\u00f8gspersoner, der modtog injektion af kontrolopl\u00f8sningen, og 14 fors\u00f8gspersoner i observationsgruppen. Fors\u00f8gspersonerne blev unders\u00f8gt med en opf\u00f8lgningstid p\u00e5 12 m\u00e5neder efter behandling. Begge interventionsgrupper viste en betydelig reduktion p\u00e5 ca. 40% i subjektive symptomer p\u00e5 t\u00f8rre \u00f8jne. Denne forbedring var betydelig allerede ved opf\u00f8lgning efter en uge og varede ved 12 m\u00e5neder efter behandling. Observationsgruppen oplevede ingen betydelig \u00e6ndring i symptomer. ASCs gruppen viste desuden en signifikant stigning i t\u00e5refilmsstabiliteten (NIKBUT) p\u00e5 6,48 sekunder (149%) ved opf\u00f8lgning efter fire uger, hvilket var markant h\u00f8jere end efter injektion af kontrolopl\u00f8sning (<jats:italic>p<\/jats:italic>\u2009=\u20090,04). Desuden viste ASCs gruppen en betydelig stigning i NIKBUT sammenlignet med observationsgruppen ved opf\u00f8lgning efter 12 m\u00e5neder (<jats:italic>p<\/jats:italic>\u2009=\u20090,004). B\u00e5de injektion af ASCs og kontrolopl\u00f8sning medf\u00f8rte en betydelig stigning i t\u00e5reproduktionen ved opf\u00f8lgning fire m\u00e5neder og 12 m\u00e5neder efter behandling. Denne afhandling bidrager med vigtige resultater inden for en ny behandlingsmulighed af t\u00f8rre \u00f8jne. Injektion af ASCs i t\u00e5rekirtlen viste sig at v\u00e6re sikker, forbedrede subjektive symptomer p\u00e5 t\u00f8rre \u00f8jne og \u00f8gede s\u00e6rligt t\u00e5rfilmens stabilitet hos patienter med ADDE p\u00e5 grund af SS. Sammenlignet med andre behandlingsmuligheder for ADDE har denne behandling vist et stort potentiale. ASCs kan muligvis ogs\u00e5 bruges som en anti\u2010inflammatorisk behandling af t\u00f8rre \u00f8jne af andre \u00e5rsager i fremtiden.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aos.15739","type":"journal-article","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T06:51:33Z","timestamp":1697439093000},"page":"3-27","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Mesenchymal stem cell therapy in aqueous deficient dry eye disease"],"prefix":"10.1111","volume":"101","author":[{"given":"Michael","family":"M\u00f8ller\u2010Hansen","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Copenhagen University Hospital \u2010 Rigshospitalet Copenhagen Denmark"},{"name":"University of Copenhagen Copenhagen 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