Surgical Procedures in the Treatment of Dry Eye Disease

Abstract

Dry eye disease (DED) is a multifactorial disease affecting 5% to 50% in different populations. The most severe cases of DED are often caused by aqueous deficient dry eye disease (ADDE) due to lacrimal gland (LG) hypofunction. Many patients with severe ADDE do not experience adequate symptom relief from topical treatment, severely reducing their quality of life. The focus of this review is to describe the surgical interventions presently being used or investigated when topical treatment with eye drops is insufficient. The conventional surgical approach is to proceed to punctal occlusion or partial or total tarsorrhaphy. However, novel surgical procedures have been reported to have higher efficacy and patient satisfaction than conventional treatments. These procedures include amniotic membrane transplantation, transposition or transplantation of the salivary glands, and cell-based injections into the LG, each with strengths and weaknesses. Further development of these treatment modalities might prove pivotal in treating dry eye patients in the future.

Introduction

Dry eye disease (DED) has been reported to affect as much as 50% of the population.¹ Symptoms of DED include a variety of ocular discomfort and blurred vision, which has a negative impact on the visual function and quality of life.² As concluded in the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) II report from 2017, DED is a multifactorial disease, in which hyperosmolarity of the tear fluid, tear film instability, and inflammation on the ocular surface leads to damage, and neurosensory abnormalities.

This further deteriorates the integrity of the tear film, leading to a vicious cycle. DED can be subdivided into evaporative dry eye (EDE), which is characterized by a decrease in tear film quality and aqueous-deficient dry eye (ADDE) characterized by a decrease in tear fluid quantity from the lacrimal gland (LG).³ The most common causes of severe ADDE are Sjögren's syndrome (SS), which is a chronic autoimmune disorder affecting the exocrine glands, and graft-versus-host disease (GvHD), and Steven Johnson syndrome (SJS).⁴

Although nonsurgical treatments are typically the first line of approach, surgical interventions may be considered for severe and refractory cases of DED that do not respond adequately to conservative therapies.⁵ Novel surgical procedures might prove pivotal for the future treatment of ADDE. In this review, we aim to present the current treatment strategies for surgical management of treatment refractive ADDE by primarily focusing on up-to-date human studies.

Eyelid Procedures

Punctal occlusion

In patients with ADDE, conservation of tears on the ocular surface can be achieved by blocking the drainage of tear fluid in the lacrimal puncta.⁶ This procedure can be performed either unilaterally or bilaterally, on the upper or lower punctum or both, and by using either punctal plugs or more permanently by surgical occlusion.^7–10 This treatment modality, however, is most likely to be successful when combined with other treatments of DED.¹¹ A Cochrane review updated in 2017 included 18 clinical trials aimed at elucidating the efficacy of punctal plug occlusion as a treatment of DED. The authors concluded that even though punctal plugs was considered a relatively safe treatment, few studies had reported punctal plugs to be effective in the treatment of DED; the aggregate evidence was inconclusive mainly due to the extensive heterogeneity in trial methodology.¹²

The most common complication related to punctal plugs is spontaneous plug displacement, occurring in as many as 70% of cases, whereas infection, conjunctivitis, subconjunctival hemorrhage, chemosis, epiphora, discomfort, and foreign body sensation were less frequent.^13–15 One concern regarding tear conservation approaches is that retention of tear fluid containing pro-inflammatory cytokines on the ocular surface could worsen the inflammatory process, driving the vicious circle of DED. One study, however, contradicts this notion as punctal occlusion resulted in reduced corneal fluorescein staining (CSF) and DED symptoms without a rise in matrix metalloproteinase 9 levels.¹⁶

Permanent surgical occlusion of the lacrimal punctum is typically reserved for patients who do not tolerate punctal plugs. The most common method is by thermal cautery; however, other options include diathermy and Argon laser.¹⁷ Permanent punctum occlusion by cauterization has been found to significantly alleviate symptoms of DED, increase tear production and tear film break-up time (TBUT), and reduce CSF in patients with ADDE. To avoid epiphora after treatment, a partial occlusion technique has been shown to improve TBUT and CSF in patients with SS.¹⁸

Tarsorrhaphy

Tarsorrhaphy is a surgical procedure in which partial or total closure of the eyelids is obtained using either sutures, adhesive tape or levator paralysis by Botulinum toxin A (BTA) injection.¹⁹ The purpose of this treatment is to decrease ocular surface exposure to keep the ocular surface lubricated and protected. As this procedure impairs the visual function on the treated eye it is reserved for patients with persistent epithelial defects and in cases of severe DED that are refractory to previous treatment. With careful patient selection, however, it does have a high success rate (>90%) with only few complications such as trichiasis, premature opening of the tarsorrhaphy, and infection.²⁰ Interestingly, only 20% of patients have reported being unhappy with the cosmetic appearance of the tarsorrhaphy, which is possibly due to the fact that it is normally reserved for cases where all other treatments have failed.²¹

Transplantations and Transpositions

Amniotic membrane transplantation

The amniotic membrane (AM) is the innermost layer of the placenta and consists of 3 layers: a monolayer epithelium, a thick basement membrane, and an avascular stroma. The AM contains various anti-inflammatory and anti-angiogenic cytokines and growth factors, which are involved in promoting epithelial wound healing.²² Amniotic membrane transplantation (AMT) has been successfully used to treat various inflammatory ocular surface diseases, including epithelial keratitis in DED, corneal ulcers, persistent epithelial defects, and limbal stem cell deficiency.²³ Initially, AMT was performed by suturing the graft to the ocular surface (Fig. 1A). More recently, cryopreserved AM (CAM) has been used as a sutureless self-retained biologic bandage lens for the cornea (Fig. 1B).

FIG. 1.

Different methods used for amniotic membrane transplantation. (A) The amniotic membrane graft (yellow) is sutured to the conjunctiva to cover the cornea. (B) The Prokera^® bandage lens where the amniotic membrane (yellow) is attached to a thermoplastic ring (green). (C) The amniotic membrane graft (yellow) is held in place by a symblepharon ring (blue) to cover the cornea and bulbar conjunctiva. Created using Biorender.com.

Further, a combination of AM transplantation kept in place using a symblepharon ring has proven effective in the acute phase of SJS (Fig. 1C).²⁴ Whereas sutured grafts gradually dissolve over the course of 12 months, sutureless AM grafts dissolve within a week.²⁵ The commercially available CAM, Prokera^® (BioTissue, Doral, FL), seems to offer a promising treatment option for patients with moderate-to-severe treatment refractive DED.²⁶ However, 1 study investigated the effect of Prokera in patients with ADDE due to SS and found that all patients experienced a relapse of symptoms after a mean of 24.6 days after removal of the Prokera.²⁷ This suggests that the anti-inflammatory effect of AM transplantation in patients with ADDE might be temporary. In the future, topical treatment with AM extract eye drops might offer an alternative approach.²⁸

Transplantation of the salivary glands

The salivary glands (SGs) share many common morphological and physiological characteristics with the LG. The composition of SG and LG secretion is similar and contains antimicrobial peptides and surface immunoglobulins that provides mucosal immunity. Tears have a pH range of 6.5–7.6, whereas the pH of saliva ranges from 5.6 to 7.0.^29,30 The similarities have led to the exploration of SG transplantation as a possible treatment of severe ADDE. The concept of using saliva to lubricate dry eyes was first employed in 1951³¹ and since then, transplantation and/or transposition of the major SGs (parotid, submandibular, and sublingual gland) and the minor labial SGs has been explored (Fig. 2).

FIG. 2.

The various transplantations and transpositions of the salivary glands are illustrated on the left side of the figure. The right side of the figure shows the normal anatomic position of the salivary glands. PG, parotid gland; SMG, submandibular gland; SG, sublingual gland; MSG, minor labial salivary glands; SMGT, submandibular gland transplantation; PDT, parotid duct transposition; MSGT, minor labial salivary gland transplantation. Created using Biorender.com

The transplantation of SGs ultimately results in the establishment of functional exocrine tissue that serves as a source of lubrication and supplies various beneficial factors present in tears to alleviate DED.³² The process of SG transplantation is intricate and challenging as it involves multiple steps such as graft harvesting, transfer, and microanastomosis. Thus, collaboration with a skilled oral surgeon or maxillofacial surgeon is required. SG transplantation should be reserved for patients with severe end-stage ADDE, which cannot be controlled by conservative means. Autologous SG transplantation is by far the most studied method.

However, this treatment is controversial in patients with ADDE due to autoimmune disorders such as SS and GvHD, which might affect the SGs as well. Allogeneic transplantation, although technically feasible, is complicated as histocompatibility is a major concern. This requires lifelong immunosuppressive treatment, which often results in complications.³³ This leaves severe ADDE without affection of the SGs as the primary indications for autologous transplantation. The indications include ADDE due to chemical injuries, SJS, cicatrizing conjunctivitis, acquired alacrimia (after excision of LG tumor), congenital alacrimia, facial nerve palsy, and idiopathic keratoconjunctivitis sicca.^31,32

Parotid duct transposition

In parotid duct transposition the secretory duct of the parotid gland (Stensen's duct) is moved from its original position in the mouth to the lower conjunctival fornix (Fig. 2).³⁴ As the innervation of the parotid gland is maintained, the ocular surface receives an exclusively serous secretion that is controlled by the gustatory reflex. As the present data mainly come from older retrospective case reports the success rate is questionable.³⁵ Complications such as gustatory reflex epiphora and complications related to the serous composition of the “salivary tears” have since led to the conclusion that techniques involving the other SGs are superior.³¹

Submandibular gland transplantation

In transplantation of the submandibular gland, the gland along with a vascular pedicle and the secretory duct is implanted under the skin of the temporal region. An anastomosis from the facial vessels is performed and the duct is then sutured into the conjunctival fornix (Fig. 2).³⁵ Submandibular gland transplantation (SMGT) has several advantages compared with other transplantations of major SGs: The “salivary tears” from the SMG grafts resemble the mucoaqueous component of the normal tear film causing fewer complications such as reflex epiphora and graft ischemia.^36,37 SMGT has been tested in several clinical trials in patients with severe ADDE and a viability in 85% to 100% of cases up to 5 years after transplantation has been reported with improvement in Schirmer test scores, TBUT, and CSF.^38–41

However, epiphora remains a common complication, why partial SMGT has been investigated. In 1 study 86% (19/22 patients) with a total submandibular gland graft suffered from epiphora versus 30% (6/20 patients) with a partial transplant.⁴² In these cases epiphora can be controlled either surgically by reducing the size of the SMG or by partial ligation of the excretory duct or pharmacologically with periglandular BTA injections or by applying atropine gel onto the skin overlying the graft.^43–45 The most significant limitation of SMGT is the hypo-osmolarity of the salivary tears, which causes microcystic epithelial edema in up to 40% of the cases.⁴⁶

Minor labial SG transplantation

The minor labial salivary glands (MSGs) reside in the labial mucosa and has been used as a complex graft (a mucosal patch including MSGs) to the fornices, palpebral, tarsal, or bulbar conjunctiva in eyes with severe ADDE (Fig. 2). Minor labial salivary gland transplantation (MSGT) has resulted in an increase in Schirmer's test score and CSF with graft viability in up to 95% of cases.³² In a larger study an improvement in visual acuity (VA) from 38% of cases with a VA ≥20/200 at baseline to 93% 3 years after MSGT was found.⁴⁷

This is in contrast to other SG transplantation methods which has not proven to improve VA. MSGT has generally been reported to carry low risk for complications; however, labial hypoesthesia at the donor site has been reported in about 2/3 of cases, whereas graft necrosis and epiphora are rare.⁴⁷ SMGT is a complex procedure, which requires collaboration with an oral maxillofacial surgeon, whereas MSGT is simpler with low surgical risk. The most significant limitation of MSGT is the limited lubrication provided.⁴⁸ In a rhesus monkey animal model, the efficacy of fluid production initially increased after transplantation, but showed a decrease during follow-up.⁴⁹

Injections

Periocular botox injection

Botulinum toxin A (botox, BTA) is a neurotoxin that blocks the release of acetylcholine at the neuromuscular junctions of cholinergic nerves, which reduces muscle contractions.⁵⁰ Although injection of BTA into the LG is a mainstay treatment of patients with hypersecretion from the LG,⁵¹ periocular injection of BTA has also been investigated as a potential treatment of ADDE. In 1997, it was first reported that periocular injection of BTA in patients with SS resulted in an increase in Schirmer test scores and a decrease in DED symptoms.⁵² It has since been proposed that injection of BTA into the medial part of the lower eyelid causes orbicularis muscle paralysis, which in turn decreases the amount of tear volume ejected at each blink.⁵³

More recently, 2 randomized clinical trials have demonstrated the efficacy of periocular BTA injection as a treatment of DED.^54,55 However, in these studies the Schirmer test scores have inconsistently shown to be both lower and higher after treatment. A recent retrospective observational study of 28 patients with DED found significant improvements in the DED symptoms, tear osmolarity, Schirmer test scores, and tear meniscus height 1 month after treatment.⁵⁶ No data on long-term results have been published, but the effect of this treatment is presumed to be temporary. Interestingly, 1 previous study has compared BTA injection with punctal plugs and concluded, that of the 2, BTA was associated with fewer and milder complications and with higher levels of patient satisfaction.⁵⁷

Platelet-rich plasma

Platelet-rich plasma (PRP) is a reservoir of biologically active growth factors, which has been proven to be effective on tissue regeneration and wound healing.⁵⁸ These regenerative properties are related to the high content of growth factor from PRP, which supports cell proliferation.⁵⁹ In an effort to target the underlying cause of LG hyposecretion in patients with ADDE, injection of autologous PRP into (or around) the LG has been tested in 2 trials in patients with SS.^60,61 In the first prospective clinical trial, 30 patients with ADDE due to SS were randomized to either (n = 15) repeated PRP injection (days 0, 30, 60, and 90) + hyaluronic acid (HA) eye drops or (n = 15) HA eye drops alone. The injections were performed transcutaneously into the external one-third of the orbital rim in the anatomical area corresponding to the location of the LG (Fig. 3B).

FIG. 3.

Routes of injection into the LG. (A) Transconjunctival injection in which the palpebral lobe of the LG is visualized beneath the conjunctiva. (B) Transcutaneous injection without visualization of the LG. (C) Transcutaneous injection in which the LG is identified using ultrasound and the position of the needle inside the LG is observed in real time. LG, lacrimal gland.

Ninety days after treatment a significant improvement in Schirmer's test scores, CSF, TBUT, and DED symptoms was found.⁶⁰ Moreover, in a recent retrospective study of 14 patients with ADDE due to SS, injection of PRP demonstrated significant improvements of the treated eye compared with the fellow eye evaluated with noninvasive TBUT, tear meniscus height, lipid layer thickness, CFS, and Schirmer test scores.⁶¹ No data on DED symptoms in the patients were reported in this study. Among the scarce clinical trials investigating PRP injection as a treatment of ADDE no long-term results have been published. Interestingly, no adverse events were reported in any of these trials.

Mesenchymal stem cells

Cell-based therapies aiming at regenerating the LG have been the topic of several investigations in preclinical studies.⁶² Most of the previous research has been performed in animal models, in which the therapeutic effect of mesenchymal stem cells (MSCs) has been demonstrated.^63–68 The regenerative effect of MSCs has been ascribed to their paracrine and immunomodulating properties—specifically it has been suggested that MSCs exert their effect by restoring the balance between pro-inflammatory Th17- and anti-inflammatory regulatory T cells.⁶⁹

In 2021, the results of the first study investigating injection of allogeneic MSCs into the LG as a treatment for ADDE in humans were published.⁷⁰ The purpose of this open-label clinical trial was to evaluate the safety and feasibility of injecting allogenic adipose-derived mesenchymal stem cells (ASCs) into the LG in patients with severe ADDE due to SS. Seven subjects received 1 transconjunctival injection of ASCs from a healthy donor into the LG in 1 eye (Fig. 3A). The primary outcome measure was safety evaluated as number of adverse reactions related to the study treatment.

Within the 4 months of follow-up in this study, no adverse reactions were observed. A significant improvement in ocular surface disease index (OSDI) score, tear osmolarity, TBUT, and Schirmer test scores in the treated eye suggest that injection of ASCs into the LG is a safe and feasible treatment of severe ADDE. To evaluate the therapeutic effect of this treatment, a randomized clinical trial using allogeneic ASCs as a treatment of ADDE due to SS was initiated in November 2020 and the results are underway.⁷¹ In this trial, a transcutaneous injection into the LG using ultrasonic guidance is performed to assure delivery of the treatment within the LG (Fig. 3C).⁷²

Conclusion

In patients with severe dry eye and insufficient response to treatment with eye drops, a surgical procedure should be considered the next step. Novel treatments, including AM transplantation and autologous transplantation of the minor salivary glands, have been reported to be successful in selected patients, but each have their limitations. In patients with severe ADDE, cell-based injections into the LG targets the underlying inflammation in ADDE and have shown promising results in human studies. Further development of treatments with cell-based injections might prove pivotal for the treatment of dry eye patients in the future.

Authors' Contributions

M.M-H. contributed to conceptualization, methodology, writing—original draft, and visualization. S.T-P. carried out conceptualization, methodology, writing—review and editing. S.H. carried out conceptualization, supervision, and writing—review and editing.

Footnotes

Author Disclosure Statement

All authors met the ICMJE authorship criteria. No honoraria or payments were made for authorship. In collaboration with Rigshospitalet and the University of Copenhagen authors M.M-H. and S.H. has filed a patent application “Stem cell therapy for lacrimal gland dysfunction” to the European Patent Office (ref. 21943EP00). M.M-H. is a member of the advisory board for Abilion Medical Systems AB. T.P.H. is cofounder and co-owner of The Norwegian dry eye clinic and the Clinic of eye health, Oslo, Norway, which delivers talks for and/or receives financial support from the following: ABIGO, Alcon, Allergan, AMWO, Bausch & Lomb, Bayer and European school for advanced studies in ophthalmology, InnZ Medical, Medilens Nordic, Medistim, Novartis, Santen, Specsavers, Shire Pharmaceuticals, and Théa Laboratories.

Funding Information

This study was funded by grants from Simon Spies Fonden, Synoptik Fonden, and Fight for Sight, Denmark.

References

Stapleton

, Alves

, Bunya

, et al. TFOS DEWS II epidemiology report. Ocul Surf, 2017; 15(3):334–365; doi: 10.1016/j.jtos.2017.05.003

Uchino

, Schaumberg

. Dry Eye Disease: Impact on quality of life and vision. Curr Ophthalmol Rep, 2013; 1(2):51–57; doi: 10.1007/s40135-013-0009-1

Bron

, de Paiva

, Chauhan

, et al. TFOS DEWS II pathophysiology report. Ocul Surf, 2017; 15(3):438–510; doi: 10.1016/j.jtos.2017.05.011

Gomes

JAP

, Azar

, Baudouin

, et al. TFOS DEWS II iatrogenic report. Ocul Surf, 2017; 15(3):511–538; doi: 10.1016/j.jtos.2017.05.004

Jones

, Downie

, Korb

, et al. TFOS DEWS II management and therapy report. Ocul Surf, 2017; 15(3):575–628; doi: 10.1016/j.jtos.2017.05.006

Tai

, Cosar

, Cohen

, et al. The clinical efficacy of silicone punctal plug therapy. Cornea, 2002; 21(2):135–139; doi: 10.1097/00003226-200203000-00001

Chen

, Shen

, Chen

, et al. Tear meniscus volume in dry eye after punctal occlusion. Invest Ophthalmol Vis Sci, 2010; 51(4):1965–1969; doi: 10.1167/IOVS.09-4349

Hirai

, Takano

, Uchio

, et al. Clinical evaluation of the therapeutic effects of atelocollagen absorbable punctal plugs. Clin Ophthalmol, 2012; 6(1):133–138; doi: 10.2147/OPTH.S28886

Chen

, Wang

, Chen

, et al. Upper punctal occlusion versus lower punctal occlusion in dry eye. Invest Ophthalmol Vis Sci, 2010; 51(11):5571–5577; doi: 10.1167/IOVS.09-5097

10.

Egrilmez

, Aslan

, Karabulut

, et al. Clinical efficacy of the SmartPlug^TM in the treatment of primary Sjogren's syndrome with keratoconjunctivitis sicca: One-year follow-up study. Rheumatol Int, 2011; 31(12):1567–1570; doi: 10.1007/S00296-010-1527-X

11.

Roberts

, Carniglia

, Brazzo

. Comparison of topical cyclosporine, punctal occlusion, and a combination for the treatment of dry eye. Cornea, 2007; 26(7):805–809; doi: 10.1097/ICO.0B013E318074E460

12.

Ervin

, Law

, Pucker

. Punctal occlusion for dry eye syndrome. Cochrane Database Syst Rev, 2017; 2017(6):CD006775; doi: 10.1002/14651858.CD006775.PUB3

13.

Kaido

, Ishida

, Dogru

, et al. Comparison of retention rates and complications of 2 different types of silicon lacrimal punctal plugs in the treatment of dry eye disease. Am J Ophthalmol, 2013; 155(4):648-653, 653.e1; doi: 10.1016/J.AJO.2012.10.024

14.

Horwath-Winter

, Thaci

, Gruber

, et al. Long-term retention rates and complications of silicone punctal plugs in dry eye. Am J Ophthalmol, 2007; 144(3):441–444; doi: 10.1016/J.AJO.2007.05.019

15.

Bourkiza

, Lee

. A review of the complications of lacrimal occlusion with punctal and canalicular plugs. Orbit, 2012; 31(2):86–93; doi: 10.3109/01676830.2011.648802.

16.

Tong

, Beuerman

, Simonyi

, et al. Effects of punctal occlusion on clinical signs and symptoms and on tear cytokine levels in patients with dry eye. Ocul Surf, 2016; 14(2):233–241; doi: 10.1016/J.JTOS.2015.12.004

17.

Geerling

, Tost

. Surgical occlusion of the lacrimal drainage system. Dev Ophthalmol, 2008; 41:213–229; doi: 10.1159/000131091

18.

Holzchuh

, Villa Albers

, Osaki

, et al. Two-year outcome of partial lacrimal punctal occlusion in the management of dry eye related to Sjögren syndrome. Curr Eye Res, 2011; 36(6):507–512; doi: 10.3109/02713683.2011.569870

19.

Kirkness

, Adams

GGW

, Dilly

, et al. Botulinum toxin A-induced protective ptosis in corneal disease. Ophthalmology, 1988; 95(4):473–480; doi: 10.1016/S0161-6420(88)33163-5.

20.

Cosar

, Cohen

, Rapuano

, et al. Tarsorrhaphy: Clinical experience from a cornea practice. Cornea, 2001; 20(8):787–791; doi: 10.1097/00003226-200111000-00002

21.

Gossman

, Bowe

, Tanenbaum

. Reversible suture tarsorrhaphy for eyelid malposition and keratopathy. Ophthalmic Surg, 1991; 22(4):237–239; doi: 10.3928/1542-8877-19910401-16

22.

Utheim

, Aass

Utheim Ø

, Salvanos

, et al. Concise review: Altered versus unaltered amniotic membrane as a substrate for limbal epithelial cells. Stem Cells Transl Med, 2018; 7(5):415; doi: 10.1002/SCTM.17-0257

23.

Tseng

SCG

, Espana

, Kawakita

, et al. How does amniotic membrane work?. Ocul Surf, 2004; 2(3):177–187; doi: 10.1016/S1542-0124(12)70059-9

24.

Singh

, Raj

, Gupta

, et al. Role of amniotic membrane transplantation in treating acute ocular manifestations in Steven-Johnson syndrome and its long-term impact. Indian J Ophthalmol, 2022; 70(12):4470–4471; doi: 10.4103/IJO.IJO_1451_22.

25.

Liu

, Sheha

, Fu

, et al. Update on amniotic membrane transplantation. Expert Rev Ophthalmol, 2010; 5(5):645–661; doi: 10.1586/EOP.10.63

26.

McDonald

, Sheha

, Tighe

, et al. Treatment outcomes in the DRy Eye Amniotic Membrane (DREAM) study. Clin Ophthalmol, 2018; 12:677; doi: 10.2147/OPTH.S162203

27.

Shafer

, Fuerst

, Massaro-Giordano

, et al. The use of self-retained, cryopreserved amniotic membrane for the treatment of Sjögren syndrome: A case series. Digit J Ophthalmol, 2019; 25(2):21; doi: 10.5693/DJO.01.2019.02.005

28.

Pérez

, Barreales

, Sabater-Cruz

, et al. Amniotic membrane extract eye drops: a new approach to severe ocular surface pathologies. Cell Tissue Bank, 2022; 23(3):473–481; doi: 10.1007/S10561-021-09962-4/FIGURES/2

29.

Silvers

, Som

. SALIVARY GLANDS. Radiol Clin North Am, 1998; 36(5):941–966; doi: 10.1016/S0033-8389(05)70070-1.

30.

Obata

. Anatomy and histopathology of the human lacrimal gland. Cornea, 2006; 25(10 Suppl 1):S82–S89; doi: 10.1097/01.ico.0000247220.18295.d3

31.

Geerling

, Sieg

. Transplantation of the major salivary glands. Dev Ophthalmol, 2008; 41:255–268; doi: 10.1159/000131094

32.

Singh

, Basu

, Geerling

. Salivary gland transplantation for dry eye disease: Indications, techniques, and outcomes. Ocul Surf, 2022; 26:53–62; doi: 10.1016/J.JTOS.2022.07.013

33.

Jacobsen

, Hakim

, Trenkle

, et al. Allogenic submandibular gland transplantation following hematopoietic stem cell transplantation. J Cranio-Maxillofacial Surg, 2013; 41(8):764–769; doi: 10.1016/j.jcms.2013.01.015

34.

Shanon

, Lazar

, Redianu

. Surgical treatment of xerophthalmia. Laryngoscope, 1973; 83(12):1999–2002; doi: 10.1288/00005537-197312000-00010

35.

Murube-Del-Castillo

. Transplantation of salivary gland to the lacrimal basin. Scand J Rheumatol, 1986; 15(Suppl. 61):264–267.

36.

Geerling

, Garrett

, Paterson

, et al. Innervation and secretory function of transplanted human submandibular salivary glands. Transplantation, 2008; 85(1):135–140; doi: 10.1097/01.TP.0000296060.39823.A4

37.

Wang

D kan

, Zhang

S en

, Su

Y xiong

, et al. Microvascular submandibular gland transplantation for severe keratoconjunctivitis sicca: A single-institution experience of 61 grafts. J Oral Maxillofac Surg, 2018; 76(11):2443–2452; doi: 10.1016/J.JOMS.2018.05.008

38.

Borrelli

, Schröder

, Dart

JKG

, et al. Long-term follow-up after submandibular gland transplantation in severe dry eyes secondary to cicatrizing conjunctivitis. Am J Ophthalmol, 2010; 150(6):894–904; doi: 10.1016/J.AJO.2010.05.010

39.

Zhang

, Su

, Cai

, et al. Factors influencing the long-term results of autologous microvascular submandibular gland transplantation for severe dry eye disease. Int J Oral Maxillofac Surg, 2019; 48(1):40–47; doi: 10.1016/J.IJOM.2018.07.006

40.

, Zhu

, Mao

, et al. Microvascular autologous submandibular gland transfer in severe cases of keratoconjunctivitis sicca. Int J Oral Maxillofac Surg, 2004; 33(3):235–239; doi: 10.1006/IJOM.2002.0438

41.

, Cai

, Yu

. Microvascular autologous submandibular gland transplantation in severe cases of keratoconjunctivitis sicca. Maxillofac Plast Reconstr Surg, 2015; 37(1):5; doi: 10.1186/S40902-015-0006-4.

42.

Qin

, Zhang

, Cai

, et al. Microvascular autologous transplantation of partial submandibular gland for severe keratoconjunctivitis sicca. Br J Ophthalmol, 2013; 97(9):1123–1128; doi: 10.1136/BJOPHTHALMOL-2013-303280

43.

Shan

, Lv

, Cai

, et al. Botulinum toxin A treatment of epiphora secondary to autologous submandibular gland transplantation. Int J Oral Maxillofac Surg, 2019; 48(4):475–479; doi: 10.1016/j.ijom.2018.07.003

44.

Cai

, Shan

, Cai

, et al. A new treatment for epiphora secondary to submandibular gland transplantation: transcutaneous atropine gel. Ocul Surf, 2014; 12(3):221–226; doi: 10.1016/J.JTOS.2014.04.001

45.

Keegan

, Geerling

, Lee

, et al. Botulinum toxin treatment for hyperlacrimation secondary to aberrant regenerated seventh nerve palsy or salivary gland transplantation. Br J Ophthalmol, 2002; 86(1):43–46; doi: 10.1136/BJO.86.1.43

46.

Geerling

, Sieg

, Bastian

, et al. Transplantation of the autologous submandibular gland for most severe cases of keratoconjunctivitis sicca. Ophthalmology, 1998; 105(2):327–335; doi: 10.1016/S0161-6420(98)93406-6

47.

Vazirani

, Bhalekar

, Amescua

, et al. Minor salivary gland transplantation for severe dry eye disease due to cicatrising conjunctivitis: Multicentre long-term outcomes of a modified technique. Br J Ophthalmol, 2021; 105(11):1485–1490; doi: 10.1136/BJOPHTHALMOL-2020-316611

48.

Wakamatsu

, Sant'Anna

AEBPP

, Cristovam

, et al. Minor salivary gland transplantation for severe dry eyes. Cornea, 2017; 36:S26–S33; doi: 10.1097/ICO.0000000000001358

49.

Qin

, Zhang

, Liang

, et al. Labial salivary gland transplantation for severe dry eye in a rhesus monkey model. Invest Ophthalmol Vis Sci, 2018; 59(6):2478–2486; doi: 10.1167/IOVS.18-23966

50.

Dutton

, Fowler

. Botulinum toxin in ophthalmology. Surv Ophthalmol, 2007; 52(1):13–31; doi: 10.1016/J.SURVOPHTHAL.2006.10.003

51.

Falzon

, Galea

, Cunniffe

, et al. Transconjunctival botulinum toxin offers an effective, safe and repeatable method to treat gustatory lacrimation. Br J Ophthalmol, 2010; 94(3):379–80; doi: 10.1136/bjo.2008.155887

52.

Spiera

, Asbell

, Simpson

. Botulinum toxin increases tearing in patients with Sjogren's syndrome: A preliminary report. J Rheumatol, 1997; 24(9):1842–1843.

53.

Sahlin

, Chen

, Kaugesaar

, et al. Effect of eyelid botulinum toxin injection on lacrimal drainage. Am J Ophthalmol, 2000; 129(4):481–486; doi: 10.1016/S0002-9394(99)00408-0

54.

Serna-Ojeda

, Nava-Castaneda

. Paralysis of the orbicularis muscle of the eye using botulinum toxin type A in the treatment for dry eye. Acta Ophthalmol, 2017; 95(2):e132–e137; doi: 10.1111/AOS.13140

55.

Choi

, Yeo

, Kang

, et al. Effects of botulinum toxin type A on the treatment of dry eye disease and tear cytokines. Graefe's Arch Clin Exp Ophthalmol, 2019; 257(2):331–338; doi: 10.1007/s00417-018-4194-3

56.

Choi

, Yeom

, Jang

. Botulinum Toxin A injection for the treatment of intractable dry eye disease. Medicina (B Aires), 2021; 57(3):247; doi: 10.3390/MEDICINA57030247

57.

Bukhari

. Botulinum neurotoxin type A versus punctal plug insertion in the management of dry eye disease. Oman J Ophthalmol, 2014; 7(2):61; doi: 10.4103/0974-620X.137142

58.

Hartwig

, Harloff

, Liu

, et al. Epitheliotrophic capacity of a growth factor preparation produced from platelet concentrates on corneal epithelial cells: A potential agent for the treatment of ocular surface defects?. Transfusion, 2004; 44(12):1724–1731; doi: 10.1111/J.0041-1132.2004.04079.X

59.

Liu

, Hartwig

, Harloff

, et al. Corneal epitheliotrophic capacity of three different blood-derived preparations. Invest Ophthalmol Vis Sci, 2006; 47(6):2438–2444; doi: 10.1167/IOVS.05-0876

60.

Avila

, Igua

, Mora

. Randomised, prospective clinical trial of platelet-rich plasma injection in the management of severe dry eye. Br J Ophthalmol, 2019; 103(5):648–653; doi: 10.1136/bjophthalmol-2018-312072

61.

Mohammed

, Allam

, Shafik Shaheen

, et al. Lacrimal gland injection of platelet rich plasma for treatment of severe dry eye: A comparative clinical study. BMC Ophthalmol, 2022; 22:343; doi: 10.1186/s12886-022-02554-0

62.

Sahu

, Foulsham

, Amouzegar

, et al. The therapeutic application of mesenchymal stem cells at the ocular surface. Ocul Surf, 2019; 17(2):198–207; doi: 10.1016/J.JTOS.2019.01.006

63.

Beyazyıldız

, Pınarlı

, Beyazyıldız Ö, et al. Efficacy of topical mesenchymal stem cell therapy in the treatment of experimental dry eye syndrome model. Stem Cells Int, 2014; 2014:1–9; doi: 10.1155/2014/250230

64.

Villatoro

, Fernández

, Claros

, et al. Use of adipose-derived mesenchymal stem cells in keratoconjunctivitis sicca in a canine model. Biomed Res Int, 2015; 2015:1–10; doi: 10.1155/2015/527926

65.

Bittencourt

MKW

, Barros

, Martins

JFP

, et al. Allogeneic mesenchymal stem cell transplantation in dogs with keratoconjunctivitis sicca. Cell Med, 2016; 8(3):63–77; doi: 10.3727/215517916X693366

66.

Jackson

, Naqvi

, Gundersen

, et al. Role of stem cells in regenerative treatment of dry eye disease caused by lacrimal gland dysfunction. Acta Ophthalmol, 2023; 101(4):360–375; doi: 10.1111/AOS.15629

67.

Sun

, Liu

, Yang

, et al. Mesenchymal stem cell transplantation alleviates Sjögren's syndrome symptoms by modulating Tim-3 expression. Int Immunopharmacol, 2022; 111:109152; doi: 10.1016/J.INTIMP.2022.109152

68.

Tian

, Hong

, Zhu

, et al. Mesenchymal stem cell enhances the function of MDSCs in experimental sjögren syndrome. Front Immunol, 2020; 11:604607; doi: 10.3389/FIMMU.2020.604607

69.

Yao

, Qi

, Liang

, et al. Mesenchymal stem cell transplantation alleviates experimental Sjögren's syndrome through IFN-β/IL-27 signaling axis. Theranostics, 2019; 9(26):8253; doi: 10.7150/THNO.37351

70.

Møller-Hansen

, Larsen

, Toft

, et al. Safety and feasibility of mesenchymal stem cell therapy in patients with aqueous deficient dry eye disease. Ocul Surf, 2021; 19:43–52; doi: 10.1016/j.jtos.2020.11.013

71.

Anonymous. Mesenchymal Stem Cell Therapy of Dry Eye Disease in Patients With Sjögren's Syndrome. n.d. Available from: https://clinicaltrials.gov/ct2/show/NCT04615455 [Last accessed: April 13, 2021].

72.

Larsen

A-C

, Møller-Hansen

, Wiencke

, et al. Ultrasound-guided transcutaneous injection in the lacrimal gland: A description of sonoanatomy and technique. J Ocul Pharmacol Ther, 2023; 39(4):275–278; doi: 10.1089/JOP.2022.0156