Abstract
Purpose
This study evaluated the feasibility and effectiveness of autologous adipose-derived mesenchymal stem cell (ASC) transplantation into the lacrimal gland for treating aqueous-deficient dry eye disease (DED) associated with Sjögren syndrome.
Methods
Patients with Sjögren syndrome–related DED underwent autologous adipose tissue harvest via liposuction. ASCs were isolated, cultured, and injected into the lacrimal gland (volume ≤50% of estimated gland volume). Clinical evaluations— including Ocular Surface Disease Index (OSDI), tear osmolarity, tear film breakup time (TBUT), Oxford corneal staining, and Schirmer test I—were conducted at 1-, 4-, 16-, and 24-weeks after injection. Visual quality assessments included contrast sensitivity and higher-order aberrations (HOAs).
Results
Six patients (mean age 56.1 ± 7.2 years) completed the study. Mean OSDI scores significantly decreased from 48.6 ± 8.4 to 28 ± 2.1. TBUT improved in both eyes (right, 3.3 ± 1.0 to 5.6 ± 1.2 seconds; left, 3.6 ± 1.0 to 6.1 ± 1.6 seconds). Schirmer test I values increased (right, 4.1 ± 0.7 to 7.8 ± 0.7 mm; left, 4.0 ± 0.6 to 7.6 ± 0.5 mm). Oxford staining scores decreased (right, 1.6 ± 0.5 to 0.67 ± 0.2; left, 1.3 ± 0.5 to 0.67 ± 0.2). Tear osmolarity also improved (right, 311.6 ± 6.1 to 299.1 ± 5.8 mOsm/L; left, 309 ± 7.6 to 298.3 ± 7 mOsm/L). HOAs were reduced in one eye. No significant change in contrast sensitivity or visual acuity was observed. No adverse events were reported.
Conclusions
Autologous ASC transplantation into the lacrimal gland appears to be a safe and promising therapeutic option for aqueous-deficient DED in Sjögren syndrome, offering significant improvement in both objective measures and patient-reported symptoms over a 6-month period.
Keywords: Adipose-derived mesenchymal stem cells, Dry eye syndromes, Lacrimal gland, Mesenchymal stem cell transplantation, Sjogren’s syndrome
Dry eye disease (DED) is one of the most common conditions among patients visiting eye clinics worldwide, with a prevalence ranging from 5% to 50% [1]. The prevalence of dry eye is higher in female patients and the elderly [2]. The causes of DED can be broadly categorized into two groups: increased evaporation of the tear film and aqueous deficiency due to reduced tear production by the lacrimal gland or a combination of both [3]. Sjögren syndrome is a major cause of aqueous deficiency worldwide, characterized by inf lammation of the lacrimal gland and its lymphocytic infiltration [4,5]. The prevalence of Sjögren syndrome ranges from 0.1% to 0.72% of the global population [6,7]. Clinically, dry eye due to autoimmune diseases can occur with or without Sjögren syndrome, presenting as a multifactorial disease accompanied by ocular irritation, fluctuating vision, tear film instability, increased tear osmolarity, and ultimately, epithelial surface diseases [8].
The most common traditional treatment for dry eye syndrome is artificial tear drops. Artificial tear drops have a short duration of action and are effective in patients with mild dry eye. The addition of high-viscosity lubricants to artificial tears increases the durability of the drops but can cause blurred vision and discomfort. Also, artificial tear preservatives, such as benzalkonium chloride or sodium perborate, can cause toxicity and damage to the conjunctival and corneal surfaces [9]. The use of punctal plugs is another treatment that blocks the puncta and prevents tear drainage. Although this method is effective in more severe cases of dry eye, in the long term, it can lead to the accumulation of inflammatory cytokines and increased tear osmolarity, ultimately exacerbating ocular surface damage [10,11]. Another treatment method is autologous serum drops, which are isolated from the patient’s blood and formulated as eye drops resembling artificial tears. However, disadvantages of this method include the lack of a standardized preparation protocol, limitations in storage conditions, and the risk of infection from prolonged patient use [12–14]. Another treatment option is anti-inflammatory drugs. Topical corticosteroids are a good short-term treatment for the symptoms of severe dry eye, but their long-term use carries a risk of increased intraocular pressure and cataract formation [15–18].
Despite the successful results of these treatments for dry eye syndrome, there are therapeutic challenges, especially in patients with Sjögren syndrome, that require the use of newer approaches. One of these approaches is regenerative medicine, which improves tissue function by repairing damaged cells. Stem cell-based therapy is one regenerative medicine approach that has shown promise in recent studies.
The use of stem cells has opened new horizons in the treatment of human diseases. Stem cells are broadly classified into two main categories based on their origin: embryonic stem cells and adult stem cells. Among the most important adult stem cells are mesenchymal stem cells (MSCs), which are involved in the repair of mesenchyme-derived tissues such as bone, cartilage, muscle, tendon, and fat. MSCs have demonstrated the ability to differentiate into various cell types under laboratory conditions. The ease of isolation, proliferation, and autologous nature of mesenchymal cells make them suitable candidates for cell therapy. Human MSCs can be obtained from adipose tissue, bone marrow, umbilical cord, dental pulp, gums, hair follicles, cornea, and embryos. In the past, bone marrow was the most important source of MSCs for tissue engineering, but in recent years, adipose-derived stem cells have gained a special place in this field because their isolation from adipose tissue is easier than from bone marrow and has fewer complications for the patient. Adipose-derived stem cells are more resistant and have a higher proliferation rate in laboratory culture conditions compared to bone marrow stromal cells [11,19,20]. Therefore, human adipose tissue, due to its easy accessibility, appropriate efficiency in cell recovery, and high differentiation potential, is a suitable source of extraocular stem cells [12]. Mesenchymal cells have immunoregulatory properties and immunosuppressive effects. In vitro studies have shown that these cells inhibit the proliferation of B and T cells and natural killer cells. These cells inhibit a variety of immune responses, such as cytokine secretion, B-cell and natural killer cell cytotoxicity, B-cell development, and antibody secretion [13].
Therefore, MSCs have potential for the treatment of ocular surface inflammatory disorders and dry eye [14–17]. The reality is that there is no definitive cure for dry eye, and most of the aforementioned treatment methods aim to reduce symptoms and prevent the progression and chronicity of the disease [18]. Considering the importance of the problem of DED, especially with changes in lifestyle, the need for more effective and safer treatments with greater efficacy and safety seems essential. All the mentioned treatment methods have advantages, disadvantages, and even side effects. Therefore, the use of a novel, effective, and efficient treatment method, such as MSC transplantation into the lacrimal gland with minimal side effects, can greatly help in addressing this unmet medical need.
Materials and Methods
Ethics statement
This prospective, interventional study was performed after approval by the Human Ethics Committee of Shahid Beheshti University of Medical Sciences (No. IR.SBMU. REC.1401.011). Under the principles of the Declaration of Helsinki and a detailed explanation of our study, consent form was received from all participants.
Population and samples
Six patients referred to Helal Hospital in 2023–2024 were included in this study. The inclusion criteria were as follows: (1) Participants must be over 18 years of age, with no sex restrictions; (2) a diagnosis of Sjögren syndrome according to the ACR/EULAR criteria; (3) Ocular Surface Disease Index (OSDI) score greater than 30; (4) Schirmer test (result of 2 to 5 mm in 5 minutes); (5) tear film breakup time (TBUT) less than 10 seconds; and (6) The lacrimal gland volume was determined using magnetic resonance imaging (MRI) in both eyes. The exclusion criteria were as follows: (1) lack of informed consent to participate in the study; (2) history of hypersensitivity to oxybuprocaine or dimethyl sulfoxide; (3) previous treatment with stem cell transplantation into the lacrimal gland; (4) patients with weakened immune systems, such as HIV-positive individuals; (5) pregnancy or plans for pregnancy within the next 2 years; (6) female patients who were breastfeeding; (7) patients with a history of systemic medication use, such as antidepressants or steroids; (8) history of using eye drops other than lubricants; and (9) any pathological condition that would exclude the patient from the study, such as ocular infections.
Clinical examinations
After selecting patients based on the inclusion criteria, all initial ocular examinations were performed. These examinations include refractive error assessment, measurement of best-corrected visual acuity (BCVA), autorefract ion using the KR-1 autoref ractometer (Topcon), retinoscopy using the Heine Beta 200 retinoscope (Heine Optotechnik), and subjective refraction.
Ocular Surface Disease Index
Symptoms of dry eye were assessed using the OSDI, which was developed at Allergan Inc. [21]. Before the patients completed the questionnaire, the questionnaire was introduced to the patients, and they were taught how to fill it out and answer its questions. To record more accurate subjective results, the OSDI questionnaire was completed by the patients under the same conditions of air temperature (20–22 °C) and constant humidity (20%–25%). The total OSDI score was then calculated with the help of the following formula: OSDI = [(sum of scores for all questions answered) × 100] / [(total number of questions answered) × 4], and determined on a scale of 0 to 100, with higher scores representing greater disability.
Tear film breakup time
To assess the stability of the tear film, the TBUT test was measured following the guidelines published in the Report of the International Dry Eye Workshop (DEWS) 2007 [22,23]. Three times for each eye were measured, and the average was recorded for each eye. Fluorescein sodium strip (Haag-Streit) was lightly moistened with a single drop of unpreserved 0.9% saline solution (from a single-dose ampule to prevent contamination) and used to touch the inferior fornix for a short time with minimal stimulation, to avoid irritation and reflex tearing. The slit-lamp magnification was set at ×10, the background illumination intensity was kept constant, and the tear film was observed under cobalt blue-filtered light. The interval (seconds) between the last complete blink and the first emergence of a randomly distributed dry spot was averaged and recorded on a special form.
Schirmer I test
For the estimation of tear production, we measured the Schirmer I test (without the use of an anesthetic) using a standard Whatman strip. Without the use of an anesthetic agent, we folded the Whatman strip from the marked end and placed it gently in the lower and outer third of the lower fornix of the eyelid without causing eye irritation or contact with the cornea. Patients were instructed to gently close their eyelids and not to move their eyes for 5 minutes, and then, the strip was removed, and the length of the wet portion was measured (milimeters per 5 minutes).
Osmolarity
Tear osmolarity was measured using the TearLab Osmolarity System (TearLab Corp.) [24]. The device’s collection pen was gently placed against the lower lateral tear meniscus to obtain a small tear sample (50 nL) according to the manufacturer’s protocol. Measurements were taken from the inferior lateral tear meniscus. This test must be taken before the instillation of any drops or dyes on the ocular surface [25]. So it is the first thing that was completed.
Corneal staining
Corneal staining based on the Oxford scale was performed. A strip of fluorescein (Haag-Streit) was moistened with a drop of unpreserved, sterile saline solution 0.9% from a single-dose ampule, and this was then used to touch the inferior fornix for a short time with minimal stimulation. Tear film was observed under cobalt blue-filtered light using a slit-lamp, set at ×16 magnification with ×10 oculars with a Haag-Streit slit-lamp. Grading scores were evaluated according to the Bron scheme (Oxford Grading Charts) [26].
Contrast sensitivity was assessed using FACT (OPTEC 6500 Contrast Sensitivity View-in Tester, Stereo Optical Co. Inc.) before and after the intervention. Corneal aberrometric parameters were evaluated using the Pentacam (Wavelight Pentacam Oculyzer).
Preparation of stem cells
The preparation protocol for stem cells was based on our previously established method with minor modifications as described below [27,28]. Approximately 250 mL of subcutaneous adipose tissue was obtained from the abdominal region under local anesthesia using standard liposuction. The harvested tissue was washed thoroughly with phosphate-buffered saline and enzymatically digested with 0.075% collagenase type I at 37 °C for 45 minutes under gentle agitation. The enzymatic reaction was neutralized with an equal volume of autologous human serum, and the suspension was centrifuged to isolate the stromal vascular fraction. Erythrocytes were removed using erythrocyte lysis buffer, and the pelleted cells were collected for further processing.
The isolated cells were cultured in Dulbecco’s Modified Eagle Medium (high glucose) supplemented with Gluta-MAX (Thermo Fisher Scientific), sodium pyruvate, 10% autologous human serum, 1% penicillin–streptomycin, and 2% amphotericin B. Cultures were maintained at 37 °C in a humidified atmosphere containing 5% CO2, and the culture medium was replaced every 3 to 4 days. When cells reached 80% to 90% confluence, they were subcultured, and fifth-passage (P5) adipose-derived MSCs (ASCs) were used for clinical application.
The harvested ASCs were used immediately after collection without cryopreservation to preserve their native viability and biological activity. Cell viability was assessed by the Trypan Blue exclusion assay, demonstrating a viability of greater than 90% in all preparations.
Immunophenotypic characterization was performed by flow cytometry using monoclonal antibodies against CD73, CD90, and CD105 (positive MSC markers) and against HLA-DR and CD45 (negative markers). The analysis demonstrated strong expression of the positive markers (CD73, CD90, and CD105; each >90%) and minimal expression of the negative markers (CD45 <3% and HLA-DR <5%), confirming the MSC phenotype.
For each lacrimal gland, a total of 22 × 106 viable ASCs suspended in sterile physiological saline were administered under ultrasound guidance. The total injection volume for each patient was determined individually based on preoperative MRI findings and corresponded to approximately 50% of the lacrimal gland volume.
Prior to clinical use, each ASC preparation underwent comprehensive quality control and product release testing, including the following: sterility testing for aerobic and anaerobic bacteria and fungi; mycoplasma detection using polymerase chain reaction; endotoxin quantification via the limulus amebocyte lysate assay; viral safety testing by donor serology and nucleic acid testing; and potency assessment, evaluating cell proliferation capacity and differentiation potential toward adipogenic and osteogenic lineages. Only preparations that fulfilled all predefined release criteria were approved for clinical administration.
All cell isolation, expansion, and preparation procedures were conducted in a Good Manufacturing Practice (GMP)-compliant cell culture facility under the supervision and regulatory oversight of the Food and Drug Organization of Iran.
Injection procedure
The technique of lacrimal gland injection and the postoperative follow-up schedule were adapted from the protocol outlined by Moller-Hansen et al. [29], with adjustments to suit the specific objectives of this study.
For each patient, after local anesthesia, an injection containing ASCs was administered through the conjunctiva into both eyes and into the lacrimal gland using a 10-mm long 30-gauge needle. ASCs were freshly prepared in a GMP-compliant cell culture facility immediately prior to transplantation. After the final washing step, the cells were gently resuspended in sterile physiological saline and transported to the operating room under a continuously maintained cold chain. To preserve their native viability and biological functionality, no cryopreservation step was applied, and the transfer from final preparation to administration was performed promptly. To ensure precise drug delivery, the injections were administered under ultrasound guidance using a Logic E10 R2 machine (GE Healthcare) equipped with a 6 to 24 MHz linear array transducer. To measure the volume of the lacrimal gland and calculate the injection amount, MRI was performed for all patients. The volume of the injected material should not exceed 50% of the lacrimal gland volume. MRI was performed for all eligible participants using a 3T Magnetom Prisma scanner (Siemens Healthineers). The imaging protocol consisted of a contrast-enhanced, 3D T1-weighted sequence that employed selective water excitation and acquired data at a high isotropic resolution of 0.9 mm. Subsequently, the lacrimal glands were manually segmented on a AW Server 3.2 workstation (GE Healthcare). This software allowed for meticulous adjustments in all imaging planes to ensure accurate delineation of the structures. Following this manual segmentation, the volumes of the lacrimal glands were automatically computed [29,30]. After surgery, topical antibiotics and steroids were prescribed for 2 to 4 weeks, depending on the patient’s recovery.
After transplantation, patients were followed up at 1 day, 1 week, and 1, 4, and 6 months after transplantation for re-evaluation. All initial ocular examinations were repeated. In this study, forms were prepared to record each patient’s information separately at each follow-up visit. Possible side effects, pain at the injection site, ocular discomfort, blurred vision, photophobia, infection, periorbital edema or paresthesia, or severe ocular redness and other related side effects, were monitored using both objective and subjective methods. The patient was advised to return to the clinic for examination by an ophthalmologist if any of the side effects were observed. Possible side effects reported by the patient or during follow-up sessions were collected and recorded on a special form prepared for recording side effects. At specified follow-up intervals, side effects were also graded based on Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0 and were recorded on a special side effect registration form. Systemic adverse events were also evaluated. No systemic injection-related adverse events were observed in any of the patients only three patients experienced mild flu-like symptoms over the complete 6-month follow-up. Adverse events are listed in Table 1. After data collection, the results before and after treatment were compared and evaluated.
Table 1.
Description of the adverse events and severe adverse events during the study period (n = 6)
| Adverse event | Baseline | Treatment* | At 1 wk | At 4 wk | At 16 wk | At 24 wk |
|---|---|---|---|---|---|---|
| Pain at injection site | 3 (50.0) | 2 (33.3) | ||||
| Grade 1 | ||||||
| Grade 2 | 1, 4 | 1, 5 | ||||
| Grade 3 | 5 | |||||
| Grade 4 | ||||||
| Grade 5 | ||||||
| Blurred vision | 1 (16.7) | 2 (33.3) | 1 (16.7) | None | ||
| Grade 1 | 1 | 3, 6 | 6 | |||
| Grade 2 | ||||||
| Grade 3 | ||||||
| Grade 4 | ||||||
| Grade 5 | ||||||
| Ocular discomfort | 6 (100) | 6 (100) | 5 (83.3) | 2 (33.3) | 2 (33.3) | None |
| Grade 1 | 2, 3, 4 | 3, 4, 6 | 3, 5, 6 | 1, 3 | 1, 3 | |
| Grade 2 | 5, 6 | 5, 6 | 1 | |||
| Grade 3 | 1 | 1 | ||||
| Grade 4 | ||||||
| Grade 5 | ||||||
| Periorbital paresthesia | 1 (16.7) | None | ||||
| Grade 1 | 1 | |||||
| Grade 2 | ||||||
| Grade 3 | ||||||
| Grade 4 | ||||||
| Grade 5 | ||||||
| Periorbital edema | 3 (50.0) | 1 (16.7) | None | |||
| Grade 1 | 4, 5 | 2 | ||||
| Grade 2 | 2 | |||||
| Grade 3 | ||||||
| Grade 4 | ||||||
| Grade 5 | ||||||
| Flu-like symptom | 1 (16.7) | 2 (33.3) | None | |||
| Grade 1 | 3† | 5† | ||||
| Grade 2 | 6‡ | |||||
| Grade 3 | ||||||
| Grade 4 | ||||||
| Grade 5 | ||||||
| Infection at injection site | None | |||||
| Bleeding from injection site | None | |||||
| Eyelid function disorder | None | |||||
| Other | None |
Values are presented as number (%) or patient number.
Within 30 minutes after treatment;
COVID-19 symptoms;
Sore throat, COVID negative.
Statistical analysis
Study data were analyzed using IBM SPSS ver. 23 (IBM Corp.). The distribution of continuous variables was evaluated with the Shapiro–Wilk test and histogram plot to determine normality. Descriptive statistics, including mean and standard deviation, were used to summarize data. A paired t-test was conducted to compare values before and after transplantation. Cohen d was computed as the effect size for the paired t-test, and calculated by the value of the test statistic divided by the square root of the number of pairs. The value 0.2 or lower shows a small effect, 0.2 to 0.5 a medium effect, and 0.8 or higher a large effect. A two-tailed p-value less than 0.05 was considered significant [31].
Results
In this study, eight patients were referred to the Helal Hospital in Tehran, Iran. Of these, six patients (all female) with a mean age of 56.1 ± 7.2 years (range, 48–65 years) were included in the study according to the inclusion and exclusion criteria, and two were excluded from the study process due to their refusal to participate in the intervention.
The mean volume of the lacrimal gland in the right eye was 0.31 ± 0 cm3 and in the left eye was 0.30 ± 0.06 cm3. The demographic characteristics of the patients are listed in Table 2.
Table 2.
Subject demographic and disease characteristics at baseline
| Patient no. | Sex | Age (yr) | Etiology | LG volume (cm3) | Injection dose (mL) | ||
|---|---|---|---|---|---|---|---|
|
|
|
||||||
| Right eye | Left eye | Right eye | Left eye | ||||
| 1 | Female | 65 | pSS | 0.2 | 0.3 | 0.1 | 0.1 |
| 2 | Female | 50 | pSS | 0.5 | 0.4 | 0.2 | 0.1 |
| 3 | Female | 48 | pSS | 0.3 | 0.3 | 0.1 | 0.1 |
| 4 | Female | 64 | pSS | 0.2 | 0.3 | 0.1 | 0.1 |
| 5 | Female | 58 | pSS | 0.3 | 0.2 | 0.1 | 0.1 |
| 6 | Female | 52 | pSS | 0.4 | 0.3 | 0.2 | 0.1 |
LG = lacrimal gland; pSS = primary Sjögren syndrome.
During the 180-day follow-up period after the injection, no side effects related to the intervention, such as pain at the injection site, ocular discomfort, blurred vision, photophobia, infection, periorbital edema, or paresthesia, or severe ocular redness were observed. The results of this study are presented in three separate sections.
Visual parameters
1) Visual acuity
Mean BCVA was 0.05 ± 0.05 logMAR in the right eye and 0.02 ± 0.04 logMAR in the left eye before injection. There was no statistically significant change in visual acuity after injection in 6-month follow-up periods ( p > 0.999). In all patients, visual acuity remained stable, and none experienced visual loss (Table 3).
Table 3.
Comparison of corrected visual acuity, OSDI, tear osmolarity, Schirmer test (TBUT), corneal staining, TBUT, contrast sensitivity, RMS HOA, and total RMS
| Characteristic | Before injection | At 24 wk | Test value | p-value | Cohen d |
|---|---|---|---|---|---|
| OSDI score | 48.61 ± 8.40 | 28.07 ± 2.16 | 5.969 | 0.002* | 2.44 |
| TBUT (sec) | |||||
| Right eye | 3.33 ± 1.03 | 5.67 ± 1.21 | −4.183 | 0.009* | 1.71 |
| Left eye | 3.67 ± 1.03 | 6.17 ± 1.60 | −3.273 | 0.022* | 1.34 |
| Schirmer test I (mm) | |||||
| Right eye | 4.17 ± 0.75 | 7.83 ± 0.75 | −11.000 | <0.001* | 4.49 |
| Left eye | 4.00 ± 0.63 | 7.67 ± 0.52 | −17.393 | <0.001* | 7.10 |
| Visual acuity (logMAR) | |||||
| Right eye | 0.05 ± 0.05 | 0.05 ± 0.05 | 0.000 | >0.999 | 0.00 |
| Left eye | 0.02 ± 0.04 | 0.02 ± 0.04 | 0.000 | >0.999 | 0.00 |
| Tear osmolarity (mOsm/L) | |||||
| Right eye | 311.67 ± 6.15 | 299.17 ± 5.85 | 8.097 | <0.001* | 3.31 |
| Left eye | 309.83 ± 7.65 | 298.33 ± 7.06 | 7.449 | 0.001* | 3.04 |
| Corneal staining (Oxford scale) | |||||
| Right eye | 1.67 ± 0.52 | 0.67 ± 0.26 | 5.477 | 0.003* | 2.24 |
| Left eye | 1.33 ± 0.52 | 0.67 ± 0.26 | 6.325 | 0.001* | 2.58 |
| RMS HOA (μm) | |||||
| Right eye | 0.55 ± 0.12 | 0.51 ± 0.15 | 1.872 | 0.120 | 0.76 |
| Left eye | 0.57 ± 0.17 | 0.49 ± 0.14 | 3.425 | 0.019* | 1.40 |
| RMS total (μm) | |||||
| Right eye | 1.93 ± 0.47 | 1.78 ± 0.45 | 2.184 | 0.081 | 0.86 |
| Left eye | 2.05 ± 0.42 | 1.91 ± 0.49 | 1.432 | 0.211 | 0.58 |
| Contrast sensitivity | |||||
| Right eye | 1.54 ± 0.31 | 1.51 ± 0.29 | 2.424 | 0.022* | 0.99 |
| Left eye | 1.50 ± 0.30 | 1.51 ± 0.28 | −0.306 | 0.762 | 0.12 |
Values are presented as mean ± standard deviation. Paired samples t-test.
OSDI = Ocular Surface Disease Index; TBUT = tear film breakup time; RMS = root mean square; HOA = higher-order aberration.
Statistically significant (p < 0.05).
2) Contrast sensitivity
Contrast sensitivity was performed at all spatial frequencies such as 1.5, 3.0, 6.0, 12.0 and 18.0 cycle per degree (CPD) using FACT (OPTEC 6500 Contrast Sensitivity View-in Tester, Stereo Optical Co. Inc.) before and after intervention (Fig. 1A, 1B). Statistically significant changes in contrast sensitivity were not observed at all spatial frequencies (1.5, 3.0, 6.0, 12.0 and 18.0 CPD) before and after intervention (Table 4). Changes in the contrast sensitivity functions were compared before and after the intervention (Fig. 2A, 2B).
Fig. 1.
Changes in mean contrast sensitivity from baseline (day 0) to 24 weeks of follow-up (180 days) in (A) the right eye and (B) the left eye.
Table 4.
Comparison of contrast sensitivity before and after treatment at different spatial frequencies
| Spatial frequency | Right eye | Left eye | Both eyes | Test value | p-value | Cohen d |
|---|---|---|---|---|---|---|
| 18 CPD | NA | NA | NA | |||
| Before treatment | 1.01 ± 0.09 | 1.01 ± 0.09 | 1.01 ± 0.08 | |||
| After treatment* | 1.01 ± 0.09 | 1.01 ± 0.09 | 1.01 ± 0.08 | |||
| 12 CPD | 1.000 | 0.339 | 0.29 | |||
| Before treatment | 1.43 ± 0.07 | 1.43 ± 0.07 | 1.43 ± 0.06 | |||
| After treatment* | 1.41 ± 0.07 | 1.43 ± 0.07 | 1.42 ± 0.07 | |||
| 6 CPD | 1.711 | 0.115 | 0.49 | |||
| Before treatment | 1.78 ± 0.06 | 1.78 ± 0.06 | 1.78 ± 0.06 | |||
| After treatment* | 1.72 ± 0.14 | 1.72 ± 0.08 | 1.72 ± 0.11 | |||
| 3 CPD | −0.285 | 0.781 | 0.08 | |||
| Before treatment | 1.83 ± 0.08 | 1.64 ± 0.27 | 1.73 ± 0.21 | |||
| After treatment* | 1.75 ± 0.00 | 1.75 ± 0.00 | 1.75 ± 0.00 | |||
| 1.5 CPD | 1.483 | 0.166 | 0.43 | |||
| Before treatment | 1.67 ± 0.06 | 1.64 ± 0.07 | 1.66 ± 0.06 | |||
| After treatment* | 1.64 ± 0.07 | 1.62 ± 0.08 | 1.63 ± 0.07 |
Values are presented as mean ± standard deviation. Paired samples t-test for both eyes. CPD = cycles per degree; NA = not applicable (assumptions of the test were not met).
Follow-up at 24 weeks.
Fig. 2.
Changes in contrast sensitivity function from baseline (day 0) to 24 weeks of follow-up (180 days) in (A) the right eye and (B) the left eye. CPD = cycles per degree.
Aberometry findings
Anterior corneal aberrations over 6 mm analytical zones, including total, third to fifth higher-order aberrations (HOAs), SA (Z4, 0), trefoil (Z3, −3) (Z3, 3), and coma (Z3, −1) (Z3, 1) aberrations of the anterior corneal surface were evaluated. Before the injection, the mean total HOAs were 0.55 ± 0.12 μm in the right eye and 0.57 ± 0.17 μm in the left eye (Fig. 3A, 3B). The total root mean square (TRMS) was 1.93 ± 0.47 μm in the right eye and 2.05 ± 0.42 μm in the left eye (Fig. 4A, 4B). After the intervention, the mean total HOAs were 0.51 ± 0.15 μm in the right eye and 0.49 ± 0.14 μm in the left eye. The TRMS was 1.78 ± 0.45 μm in the right eye and 1.91 ± 0.49 μm in the left eye (Table 3).
Fig. 3.
Changes in root mean square (RMS) of higher-order aberration (HOA) from baseline (day 0) to 24 weeks of follow-up (180 days) in (A) the right eye and (B) the left eye.
Fig. 4.
Changes in total root mean square (TRMS) of higher-order aberration from baseline (day 0) to 24 weeks of follow-up (180 days) in (A) the right eye and (B) the left eye.
Tear film parameters
1) Breakup time
Before the injection, the average TBUT was measured in both eyes. The mean TBUT was 3.3 ± 1.0 seconds in the right eye and 3.6 ± 1.0 seconds in the left eye. After the intervention, a significant increase in the average TBUT was observed, and the highest amount reached 8 seconds after the intervention at the last follow-up. The mean TBUT increased to 5.6 ± 1.2 seconds in the right eye and 6.1 ± 1.6 seconds in the left eye (Fig. 5A, 5B).
Fig. 5.
Changes in tear film breakup time (TBUT) measures from baseline (day 0) to 24 weeks of follow-up (180 days) after injection in (A) the right eye and (B) the left eye.
2) Schirmer test
For all patients, Schirmer test I (without the use of anesthetic drops) was performed to measure baseline tear secretion before the intervention and during the 1-, 4-, and 6-month follow-up periods. The mean Schirmer test I measured over 5 minutes increased from 4.1 ± 0.7 in the right and 4.0 ± 0.6 in the left eye before injection to 7.83 ± 0.6 and 7.6 ± 0.5 in the last follow-up, respectively (Fig. 6A, 6B).
Fig. 6.
Changes in Schirmer test I measures from baseline (day 0) to 24 weeks of follow-up (180 days) after injection in (A) the right eye and (B) the left eye.
3) Tear osmolarity
The mean tear osmolarity was 311.6 ± 6.1 and 309.8 ± 7.6 in the right and left eyes. After the intervention, the mean tear osmolarity was 299.1 ± 5.8 and 298.3 ± 7.0 in the right and left eyes, respectively, after the 6-month follow-up (Fig. 7A, 7B).
Fig. 7.
Changes in tear osmolarity measures from baseline (day 0) to 24 weeks of follow-up (180 days) in (A) the right eye and (B) the left eye.
4) Corneal staining
Corneal staining based on the Oxford scale was performed according to the Oxford criteria before the intervention and at intervals of 1, 4, 16, and 24 weeks after the stem cell injection. The mean score before the intervention was 1.6 ± 0.5 and 1.3 ± 0.5 in the right and left eyes, respectively. After the intervention, the mean score decreased to 0.6 ± 0.2 in the right eye and 0.6 ± 0.2 in the left eye at the end of the 6-month follow-up. The results showed that the corneal staining rate decreased significantly after the 6-month follow-up (Fig. 8A, 8B).
Fig. 8.
Changes in corneal staining from baseline (day 0) to 24 weeks of follow-up (180 days) in (A) the right eye and (B) the left eye.
5) Ocular Surface Disease Index
The OSDI questionnaire was used to assess subjective symptoms of dry eye and compare them before and after the intervention in the follow-up periods. The mean OSDI score decreased from 48.6 ± 8.4 before injection to 28 ± 2.1 in the last follow-up (Fig. 9). This represents a 49% reduction in OSDI score at the final follow-up compared to baseline.
Fig. 9.
Changes in Ocular Surface Disease Index (OSDI) scores before injection (day 0) to 24 weeks of follow-up (day 180).
Discussion
DED is defined as a multifactorial disorder of the ocular surface characterized by tear film instability and ocular discomfort. In this multifactorial disorder, a vicious circle of tear film instability, hyperosmolarity, ocular surface damage, neurosensory abnormalities, and inflammation occurs, each contributing to the disruption of ocular surface homeostasis. Sjögren syndrome is a chronic autoimmune disorder in which the hallmark is lymphocytic infiltration of the lacrimal and salivary glands, leading to dry eyes and mouth [32]. In this research, we assessed the safety and efficacy of transplantation of ASCs into the lacrimal gland in patients with aqueous-deficient DED associated with Sjögren syndrome.
Our results showed that transplantation of autologous ASCs into the lacrimal gland in patients with DED due to aqueous tear deficiency associated with Sjögren syndrome is an effective and safe procedure. At 6-month follow-up, TBUT and Schirmer test findings showed a significant increase, while the OSDI and tear osmolarity significantly decreased. Also, an improvement in corneal staining according to the Oxford scale was observed. In assessments, the patients’ aberrometric indices decreased moderately in the right eye and substantially in the left, which is due to the improvement of the tear film and the reduction of ocular surface irregularities. Although the patients’ tear film indices improved, there was no statistically significant change in visual acuity and contrast sensitivity. In addition, at the 6-month follow-up, none of the patients had any adverse events related to the intervention.
The evaluation of treatment outcomes using Cohen d revealed meaningful clinical improvements in patients with aqueous-deficient DED secondary to Sjögren syndrome, following transplantation of ASCs into the lacrimal glands.
In the assessment of tear function, both TBUT and Schirmer test results improved markedly. The effect sizes were large to very large (TBUT, d = 1.708 in the right eye and d = 1.336 in the left eye; Schirmer, d = 5.091 and d = 7.103, respectively), pointing to enhanced tear film stability and increased tear secretion. The OSDI, which captures patient-reported symptoms, also demonstrated a strong improvement, with a very large negative effect size (d = −2.559), indicating reduced subjective discomfort and dryness.
Additionally, in contrast sensitivity testing across different spatial frequencies, very large (d = 1.43) and large (d = 0.85) effect sizes were observed at 3 CPD (right eye) and 6 CPD (left eye), respectively. These findings suggest potentially meaningful improvements in visual performance, despite the absence of statistically significant changes at some frequencies (Table 4).
Tear osmolarity, an important marker of tear film health, showed a similarly notable reduction, with large negative effect sizes in both eyes (right eye, d = −3.454; left eye, d = −2.921). Corneal staining scores, used to assess epithelial damage, also declined significantly (right eye: d = −2.236; left eye: d = −2.586), reflecting restoration of corneal surface integrity.
Interestingly, visual acuity measured by the logMAR scale remained unchanged after treatment (d = 0.000 in both eyes). This result was expected, as the therapeutic strategy aimed primarily to improve the quality and composition of tears and alleviate surface inflammation—not to alter refractive status or impact retinal function.
Regarding optical quality, a reduction in HOA and TRMS values was observed following intervention. HOA decreased moderately in the right eye (d = −0.788) and substantially in the left (d = −1.393), while RMS total showed a large effect in right eye (d = −0.881) and a moderate effect in left eye (d = −0.560). These findings suggest that enhanced tear stability may have contributed to measurable improvements in visual quality at the optical level.
Overall, the results support the clinical benefit of ASC therapy in managing DED associated with Sjögren syndrome. Improvements were notably observed in tear secretion, osmolarity, and ocular surface health, underscoring the potential of regenerative approaches in treating severe forms of dry eye.
The findings of our study are consistent with the results of Moller-Hansen et al. [29]. Moller-Hansen et al. [29] investigated the safety and feasibility of transplanting MSCs into the lacrimal gland in five patients with aqueous-deficient DED. The study was conducted on individuals over 18 years of age with an OSDI score greater than 30, a Schirmer test I result of 2 to 5 mm in 5 minutes, and a TBUT of less than 10 seconds. The results showed that tear osmolarity decreased, and TBUT increased. Additionally, the Schirmer test I results showed significant improvement and increased tear secretion. In addition, by comparing objective and subjective symptoms between the injected eye and the other eye, no significant changes were observed in the untreated eye. In some studies conducted on dry eyes, no significant relationship was observed between signs and symptoms of dry eyes, while in our study, a clear relationship was observed between signs and symptoms of dry eyes after MSC transplantation [33].
MSCs have many advantages, including immunomodulatory properties and the ability to differentiate into a variety of cell types. MSCs decreased the number of interferon γ (IFN-γ)–secreting CD4+ cells in vivo and suppressed CD4+ cell proliferation and IFN-γ+CD4+ cell differentiation in vitro. CD4+ cells play an important role in ocular surface inf lammation, including in dry eye syndrome. Several studies have been published on the effect of MSCs injections on the lacrimal gland. MSCs have been tested in mice [34,35].
Lee et al. [17] investigated the protective and anti-inflammatory effects of MSC transplantation in mice with experimentally induced dry eye. To induce inflammation due to dry eye, 10 μL of concanavalin A, a T-cell mitogen, was injected into the lacrimal gland of the mice. After 1 week, tear production and the health of the conjunctival and corneal epithelium were assessed, and inflammatory cytokines were measured. The results showed that the injection of 10 mg/mL caused severe infiltration of CD3+ T cells in the ocular glands and significantly reduced tear secretion. Following MSC transplantation, tear production significantly improved, and the levels of cytokines and interleukin 2 IFN-γ, along with corneal staining, significantly decreased. Additionally, the analysis of the results showed that the CD3+ cell counts also decreased significantly. A significant increase in the number of goblet cells was observed after transplantation compared to pre-transplantation counts. This study demonstrated that MSC transplantation increased tear secretion and reduced inflammation and its complications in mice with experimentally induced dry eye [17]. In another study by Dietrich et al. [34], the effect of MSC transplantation on the lacrimal gland in mice with surgically induced dry eye was investigated. This study showed that MSC transplantation led to the formation of new cells and reduced inflammation in the lacrimal gland of the experimental mice. Additionally, the number of acinar structures significantly increased [34].
In this study, in addition to examining the direct effects of stem cell injection on tear quality and quantity, its indirect effects on patients’ contrast sensitivity through possible changes in tear quantity and quality were investigated. No statistically significant changes in contrast sensitivity were observed at all spatial frequencies (1.5, 3.0, 6.0, 12.0, and 18.0 CPD) before and after intervention. Studies have been conducted on the effects of using various types of artificial tear drops in short-term and long-term periods after using various types of artificial tear drops in normal individuals and patients with dry eye. The results of these studies showed an improvement in contrast sensitivity after using artificial tear drops [36–38]. Zhang et al. [39] investigated the short-term effect of artificial tears on contrast sensitivity in patients with Sjögren syndrome. The results of this study showed that the effects of artificial tears on measured contrast sensitivity in dry eye patients in the postinstillation period of 5 minutes to 4 hours appear limited, but an artificial tear with more mucoadhesive properties showed more benefit than those that do not. Most effects on contrast sensitivity were noted at medium spatial frequencies, particularly with the more mucoadhesive formulations of eye drops [39].
In our study, in addition to examining the objective and subjective results of stem cell injection on tear quantity and quality and its effect on quality of life through the OSDI questionnaire, the results of the injection on the patients’ visual quality were evaluated by evaluating HOAs and contrast sensitivity before and after stem cell injection. Whereas in previous studies, such as Moller-Hansen et al. [29], only the results of stem cell injection on tear quantity and quality, and improvement in quality of life have been evaluated.
The tear film, as the first refractive surface of the eye, plays an important role in creating a regular optical surface and creating a high-quality image on the retina [40]. Several studies have shown that changes in the tear film of patients with dry eye cause an increase in HOA compared to normal individuals. Increased HOA can reduce the optical quality of images formed on the retina and impair visual quality [39,41,42]. Montes-Mico et al. [37] investigated ocular wavefront aberrations of normal and dry eyes. The results of this study showed that dry eye patients had greater optical aberrations compared with normal control eyes, which is consistent with the results obtained in our study.
In summary, we have described a novel, effective, and efficient treatment method using MSC transplantation into the lacrimal gland with minimal side effects for treating aqueous-deficient DED associated with Sjögren syndrome. There were also limitations in our study. The age of the patients included in the study was between 48 and 56 years. In fact, the results were obtained in the middle-aged range. Other limitations of this trial include a small number of subjects, the lack of a placebo comparison, and an open-label and unblinded study design. However, future investigation with a double-blinded, randomized clinical trial and controlled study design, different age groups, with long-term follow-up may lead to more accurate, reliable, and comprehensive results.
In conclusion, this study suggests that transplanting autologous ASCs into the lacrimal gland in patients with aqueous-deficient DED may be a safe and effective treatment option for dry eye syndrome associated with Sjögren syndrome. The injection of ASCs resulted in significant improvement in objective and subjective signs and symptoms of DED after 6-month follow-up. This improvement resulted in increased tear film stability and improved lacrimal gland secretory function. Significant increases in measured TBUT and Schirmer test, with a decrease in OSDI, osmolarity, and corneal staining based on the Oxford scale, were seen. MSCs have immunomodulatory and immunosuppressive effects that reduce and control inflammation, ultimately controlling the complications of dry eye. No adverse events were observed in the 6-month follow-up.
Footnotes
Conflicts of Interest:
None.
Acknowledgements:
This work was supported by the Student Research Committee, Department of Optometry, Faculty of Rehabilitation, Shahid Beheshti University of Medical Sciences (No. IR. SBMU. RETECH.REC. 1399. 024).
Funding:
None.
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