Bilateral Sutureless Application of Human Dehydrated Amniotic Membrane with a Specialised Bandage Contact Lens for Moderate-to-Severe Dry Eye Disease: A Prospective Study with 1-Month Follow-Up

Introduction

Dry eye disease (DED), a multifactorial disease of the ocular surface, is characterised by a disrupted tear film homeostasis leading to a range of symptoms such as discomfort, visual disturbance, and tear film instability. This instability, accompanied by hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play pivotal roles in the aetiology of DED.¹

Recent epidemiological data indicate a significant increase in the prevalence of DED over the past decade. Previously affecting 5–35% of individuals aged 50 or older,² current research now suggests a prevalence rate as high as 5–50% in the general population.³ This significant rise, attributed to factors including ageing populations, environmental changes, and increased screen time, underscores DED’s escalating status as a public health challenge. The annual healthcare cost of managing DED in the U.S. alone is estimated at $3.84 billion, with wider societal cost reaching $55.4 billion,^4,5 emphasising the need for more effective and accessible treatment strategies.

The pathophysiology of DED involves a detrimental cycle where tear hyperosmolarity leads to ocular surface epithelial cell damage, triggering inflammatory responses that exacerbate tear film instability, ocular surface damage and symptomatology.^6,7 This cascade is compounded by goblet cell loss^8,9 and epithelial cell apoptosis,^10,11 which impair glycocalyx mucin expression essential for tear film stability. Clinically, this damage manifests as punctate epitheliopathy and lid wiper epitheliopathy (LWE) from mechanical stress between the lid margin and the ocular surface, further worsening symptoms.^6,7 If untreated, DED can lead to increased corneal nerve stimulation, causing discomfort, increased blinking, and a possible compensatory increase in lacrimal tear film stimulation and secretion.

The Tear Film and Ocular Surface Society (TFOS DEWS II) outlines a stepwise management approach for treating DED ranging from basic education and environmental changes (Step 1) to advanced biologics and surgical interventions (Step 4).¹² Amniotic membrane (AM) transplantation has emerged as a promising step 4 (biologics) treatment option.¹² AM, obtained post-elective caesarean delivery and processed into an allograft material,¹³ possesses unique immunomodulatory, anti-inflammatory, anti-fibrotic, pain-reducing and epithelial healing properties,^14,15 making it ideal for ocular surface healing,^16,17 benefits which can be exploited in the management of DED.¹⁸

Traditional AM products in ophthalmology, however, require specialised storage and/or application, limiting their widespread adoption as a DED treatment. Addressing these limitations, this study introduces a novel approach using Omnigen^®, a room-temperature stable dehydrated AM (dAM), applied using a specialised bandage contact lens (sBCL), OmniLenz^® (both NuVision^® Biotherapies, Nottingham, UK). This innovative technique allows consistent sutureless and surgery-free application, enhancing accessibility and convenience of AM at an earlier stage of DED. The real-world clinical benefits of this approach have already been demonstrated in refractory persistent epithelial defects,¹⁹ and early intervention in acute chemical burns.²⁰

This study aimed to evaluate the effectiveness of bilaterally applied dAM in managing signs and symptoms of DED in patient’s refractory to conventional treatments. This study therefore seeks to fill a critical gap in DED management, potentially reshaping therapeutic strategies for this increasingly prevalent condition.

Materials and Methods

Study Compliance

This study adhered to the tenets of the Declaration of Helsinki and received Aston University Research Ethics Committee (#1612) and governance approval.

Participant Selection

Participants included in the study were at least 18 years old with, more than 1 year of longstanding positive diagnosis of DED intransigent to TFOS DEWS II stage 1 treatment, an Ocular Surface Disease Index (OSDI) score of between 25 and 80, the presence of at least 1 of the following signs; corneal (≥5 punctate spots) or conjunctival (≥9 punctate spots) staining (oxford scale), or non-invasive Keratograph breakup time (NIKBUT, ≤8 seconds), and with no changes in DED therapy in the 6-weeks prior to their baseline visit. Exclusion criteria included a history of ocular herpetic keratitis, ocular surgery or IPL (Intense Pulsed Light) within 6 months prior to baseline visit, current use of glaucoma medication or other medication known to alter the tear film,³ use of moisture chamber goggles, known sensitivity to dAM antibiotics (gentamicin, imipenem, nystatin, polymyxin B and vancomycin), active ocular surface pathologies other than DED, eyelid abnormalities or extensive ocular scarring. Eligible participants were enrolled after providing written informed consent.

Study Design and Powering

This prospective pre-post interventional study was designed to select refractory DED patients who exhibited stable but chronic signs and symptoms in the month leading up to the treatment. This 1-month pre-treatment period served as a control, establishing a baseline against which changes post-treatment were assessed. The study involved 5 visits: Baseline (day −30) – initial measurements to establish control data; Treatment 1 (day 0) – repeat assessment to confirm disease stability, and application of the intervention; Treatment 2 (day 4–5) – reapplication of the intervention; Treatment removal (day 8–10) – removal of the intervention to transition into post-treatment observation; and, 1-month post-treatment follow-up (day 30) – final assessment to evaluate the outcomes of the intervention.

Both eyes were treated bilaterally, but to ensure consistent and standardised data comparison, only the right eye data was analysed. This approach aligns with common practices in ocular studies and ensures a reliable data set for analysis. The choice of the right eye was based on preliminary findings that suggested similar disease progression in both eyes of the target patient population.²¹

The required sample size was determined to be 33 participants. Power calculations were performed using G*Power v3.1, with OSDI as the primary outcome measure, based on detecting a minimally clinically important difference of 4.5 to 7.3,²² with 95% power (β = 0.05) at a two-sided statistical significance level of 5% (α = 0.05) using a pair t-test.

Intervention

Intervention involved all patients receiving two consecutive 4–5-day bilateral applications of Omnigen^® VIEW dAM (17mm diameter disc with a 6mm central aperture) applied using OmniLenz^® sBCL (18mm diameter, 8.80 base radius; plano lens; Menicon 72 material), both from NuVision^® Biotherapies, Nottingham, UK. The uniqueness of this study lies in its use of a bilateral approach made possible both using a 6mm diameter central window in the dAM disc to reduce the impact on the participant’s vision, and a specialised propriety lens modified retain dAM at the ocular surface, which distinguishes it from traditional unilateral methods.

The ocular surface was anesthetised with proxymetacaine hydrochloride 0.5%, to minimise discomfort during treatment application and treatment was applied as per manufacturer’s recommendations. Contact lens fitting, and dAM positioning, were assessed on a digital slit lamp (CSO Phoenix, Firenze, Italy) under 16x magnification, and an assessment of dAM window-to-pupil centration was checked additionally with an anterior segment Optical Coherence Tomographer (Cirrus-HD OCT, Germany). The choice of two consecutive treatments was based on previous findings suggesting that dAM benefits typically last 3–9 days, and to avoid dAM cloudiness due to accumulation of inflammatory coagulum.^23–26 The Omnilenz^® and any residual dAM was removed following instillation of anaesthetic after treatment 1 (day 4–5), and after treatment 2 (day 8–10).

Measurements

Clinical assessments were performed at baseline (day −30), on the treatment day (day 0) and 1-month post-treatment (day 30). To ensure consistency in testing conditions, all assessments were conducted by a single clinician at the same location, maintaining a mean ± SD room temperature of 21.5±1.5°C and relative humidity of 43.2±11.6%. Participants acclimatised to the room conditions for a minimum of 15 minutes before testing.²⁷

The sequence of testing followed the TFOS DEWS II recommendations, adhering to an ascending order of invasiveness.²² The testing order involved: OSDI, Dry Eye Questionnaire 5-item (DEQ-5), and Symptoms Analysis iN Dry Eye (SANDE, frequency and severity) questionnaires, used as recommended by their respective manufacturers; Tear meniscus height (TMH), measured using infrared light and high magnification digital imaging, with an average of three measurements taken from the lower lid edge below the iris using calibrated digital callipers; NIKBUT, captured by observing the time taken for a >5% distortion in Placido disc reflections, averaged over three readings following two non-forceful blinks; lipid layer thickness (LLT), graded using tear film interferometry on the modified Guillon-Keeler grading system – 0 (non-visible/absent), 1 (open meshwork), 2 (closed meshwork), 3 (wave/flow), 4 (amorphous), or 5 (coloured fringes);²⁸ limbal and bulbar hyperaemia, were automatically and objectively assessed using the R-Scan blood vessel redness detection module and classified using the JENVIS grading scale, to 0.1 precision;²⁹ Corneal staining (CornS) and conjunctival staining (ConjS) evaluated using fluorescein (BioFluoro. Biotech Vision Care Pvt., India)³⁰ observed under blue light with a yellow filter³⁰ and Lissamine strips (GreenGlo, Omni Lens Pvt, India), respectively, and the number of CornS and ConjS punctate spots subjectively graded as per the modified Oxford grading scheme;³¹ lid wiper epitheliopathy staining (LWE) was subjectively graded relative to Korb’s grading scale.³² All ocular surface and tear film metrics were assessed with an Oculus Keratograph 5m (Wetzlar, Germany); Visual Acuity was assessed in all visits for safety with an Early Treatment Diabetic Retinopathy Study LogMAR chart.

Statistics

Data analysis was performed using IBM SPSS Statistics version 26 (New York, USA). Where normal distribution had been confirmed by the Kolmogorov–Smirnov test (p > 0.05), a repeated paired sample t-test was used. A two-tailed p-value of p <0.05 was considered significant.

Results

A total of 35 eligible participants (23 females, 12 males), with a mean age of 50.3±17.5 years (range: 19–77), were included in the study. This exceeded the target sample size of 33, thus ensuring adequate study power.

All study participants had been diagnosed with DED which had been active for an average of 12.5±4.5 years and were refractory to previous treatments. None of the participants changed their concurrent treatment during the study.

Baseline (day −30), pre- (day 0) and post- (day 30) treatment characteristics are listed in (Table 1). The mean (± SD) duration of treatment (sBCL+dAM) remained in the eye was 4.1±1.5 days (range: 1–9) for the first application, and for 4.2±1.6 (range: 1–8) days for the second application, totalling an average of 8.1±2.7 (range: 4–16) days.

Table 1 Clinical Measurements Pre and Post (1 Month) of BCL+dAM Treatment.

Dry Eye Symptomatology

Significant improvements were observed in dry eye symptomatology 1-month post-treatment initiation. OSDI scores (Figure 1) decreased by 42% (p<0.01), whilst SANDE frequency (Figure 2) and severity scores (Figure 3) decreased by 33% and 31% (both p=0.01), respectively. DEQ-5 score (Figure 4) also showed a significant reduction of 32% (p=0.045) at the 1-month visit. A slight score change from baseline to treatment day was noted (p=0.035) even though no treatment was provided in the baseline visit (Table 1).

Figure 1 Subjective OSDI symptomatology score change from baseline to after treatment. *Denotes statistical significance.

Figure 2 Subjective frequency of symptoms change from baseline to after treatment. *Denotes statistical significance.

Figure 3 Subjective severity of symptoms change from baseline to after treatment. *Denotes statistical significance.

Figure 4 Subjective DEQ-5 symptomatology score change from baseline to after treatment. *Denotes statistical significance.

Ocular Surface Signs

The treatment positively impacted various ocular surface signs (Table 1). At the 1-month follow-up, the sagittal width of the LWE (Figure 5) significantly decreased from grade 1.7 to 1.1 (38% reduction, p=0.011) and a marked, but not significant, reduction in ConjS was also shown from 1.6 to 1.3 (p=0.094).

Figure 5 Objective epitheliopathy score change from baseline to after treatment.*Denotes statistical significance.

A small but significant decrease in conjunctival bulbar temporal hyperaemia from 1.10 to 0.98 (p=0.031) was noted from baseline to treatment day. There were no other significant changes on bulbar conjunctival hyperaemia, ocular surface staining or tear film lipid layer thickness pattern.

Safety

There were no significant changes in visual acuity between visits (p=0.627 and p=0.102), suggesting that the treatment was well-tolerated without adverse effects on vision. No safety concerns were raised from the treatment.

Discussion

The use of AM in clinical ophthalmology is a well-established practice for various ocular surface disorders.^16,17 Sutureless applications of AM are also gaining traction, particularly in disorders such as, persistent corneal epithelial defects,^19,33 chemical and thermal burns,^25,34 Stevens-Johnson/toxic epidermal necrolysis,^35,36 neurotrophic keratitis,³⁷ ulcerative keratitis,³⁸ limbal stem cell deficiency,³⁹ neuropathic corneal pain,⁴⁰ and recently, DED.^18,41

Recently, the use of Omnigen^® dAM applied with sBCL (OmniLenz^®), has expanded its application, especially in treating of persistent corneal epithelial defects and acute chemical burns.^19,20,42 These advancements demonstrated the safety and efficacy of extended application periods of 7 to 22 days, yielding more enhanced healing responses compared to traditional self-retained sutureless AM (Prokera, BioTissue, USA).^19,20,42

This study contributes significantly to the literature by being the first to employ dAM and using bilateral sutureless application in moderate-to-severe DED treatment. This approach not only leverages the benefits of dAM without surgical intervention but also aligns with the trend towards less invasive treatments in ophthalmology, whilst presenting a more accessible, cost-effective, and patient-friendly option for DED management.^18,41

The notable 42% (23.5 point) improvement in OSDI scores, observed in this study is comparable to, and in some cases exceeds, the outcomes from other treatments involving sutureless cryopreserved AM, such as Prokera, for DED management (Table 2). For example, in a retrospective case series by Cheng et al,⁴³ reported immediate 46% (15.3 points) improvement in OSDI scores following the removal of Prokera. However, the long-term benefit was not sustained, with OSDI scores reverting to baseline within an average of 4.2 ± 4.7 months. Notably, the initial severity of DED in this study, indicated by an OSDI score of 51.5, was higher than that reported by Cheng et al, where the OSDI score was 33 (Table 2). This suggests that, relative to the starting severity, this study achieved a more substantial improvement in symptomology, as measured by OSDI.

Table 2 Comparison of Published Moderate-to-Severe DED Study Data.

Additionally, John et al⁴⁵ reported a reduction in patient symptomatology measured by the Visual Analog Scale (VAS) from 7.1±1.5 to 2.2±1.1, one month post-treatment with Prokera Slim, though OSDI was not a measured outcome in their study. In a retrospective case series of 10 eyes, Morkin et al⁴⁰ applied Prokera Slim and Prokera Clear (2 eyes) in a study on DED-related neuropathic corneal pain, reporting effective pain control in 80% of tested eyes at 6.0±2.1 months.

In contrast, this study not only improved overall OSDI scores but it has also effectively reduced pain frequency and severity, as measured by the SANDE questionnaire, suggesting a more comprehensive and sustained symptom relief using bilateral dAM application.⁴⁰ The limited improvement in signs matches that found by Craig et al, where symptoms improved within a month of artificial tear treatment, LWE within two months, but NIKBUT and corneal/conjunctival staining took 4 months to improve.⁴⁶ Hence, the lack of change within these tear film homeostasis indicators would be expected.

The safety profile of both dehydrated and cryopreserved AM placements has been well documented, with no significant adverse reactions.⁴⁷ The use of sutureless sBCL as a delivery mechanism in this study potentially enhances patient comfort and treatment efficacy,^19,33 in contrast to previous methods involving more rigid delivery systems, such as Prokera, associated with discomfort and shorter treatment durations.^40,48 Though previously associated with reduced pain relief,^40,45 recent research suggests that the duration of treatment might not correlate with treatment benefits,⁴¹ which is possibly due to the rapid loss of beneficial proteins in cryopreserved amnion, a limitation not present in dAM.^23,49,50

The ability to deliver bilateral treatment with the dAM discs central 6mm aperture and sBCL amnion retention capability, is a unique aspect of this study, allowing clear visual axis maintenance and enabling patients to continue daily activities, thereby improving quality-of-life. This feature distinguishes the current study from other treatments that can potentially decrease vision from −0.22±0.06 to 0.92±0.45 (logMAR).⁴⁸ Though Prokera Clear previously offered similar visual and clinical benefits (in 2 cases), it was not applied bilaterally.⁴⁰ Furthermore, this bilateral treatment approach offers practical advantages in terms of potentially reducing the number of appointments or providing the option to increase the number of treatments in the current care pathway.

While soft “bandage” contact lenses have been used to protect the cornea, improve comfort, tear film stability, pain and aid epithelial recovery in many ocular surface disease states,^51,52 research demonstrated the benefit in symptoms over no lens (after cataract surgery) was <5 OSDI points.⁵³ Hence, the substantial improvements in symptomology observed in this study (of ~20 points) can be reasonably attributed to the combined use of dAM and sBCL, emphasising the efficacy of this novel treatment approach.

The increasing prevalence of DED and its impact on patient quality-of-life and healthcare systems, especially post-COVID-19, further underscores the need for effective and efficient treatment strategies.⁵⁴ The novel outpatient application of sutureless AM offers potential clinical service benefits,¹⁹ and may be preferable to current standard treatments like cyclosporin due to better clinical outcomes and lower societal costs.⁵⁵ The methodology presented in this study, applicable in a primary care setting by trained eye care practitioners, such as optometrists, offers the potential for reduced treatment costs and improved patient outcomes, thereby alleviating the economic burden on public healthcare systems.^54,55

While this prospective pre-post study offers promising standardised results, it is limited by its short-term post-treatment assessment and the lack of a more rigorous randomised control group. Further research is necessary to explore the long-term benefits of the treatment in DED including in its impact on subclinical inflammation and corneal nerves.⁴⁵

Conclusion

In conclusion, this is the first study to demonstrate the effectiveness of bilateral application of sutureless dAM using a specialised lens vehicle in reducing symptomatology and improving ocular surface health in moderate-to-severe DED. This approach has the potential to transform therapeutic strategies for DED, offering an effective and patient-friendly treatment alternative.