1. Introduction
PCEDs are defined as the failure of the re-epithelialization of the cornea within 14 days of standard care after an insult or injury [1,2,3]. The annual incidence of PCEDs in the United States is estimated to be less than 100,000 cases [4]. The condition arises from a diverse array of etiologies, including limbal stem cell deficiency (LSCD), autoimmune diseases, systematic inflammatory diseases, adhesion dysfunction, recurrent corneal damage from repeated mechanical trauma, and neurotrophic damage [1,5]. Neurotrophic changes to the trigeminal nerve could be secondary to infectious causes (HSV, HZV, acanthamoeba), systemic diseases (diabetes mellitus), iatrogenic etiologies (ocular surgeries, medication induced), neurologic reasons (trigeminal nerve palsy), and congenital diseases (congenital corneal hypoesthesia) [6]. Although the exact percentage of different PCED etiologies is unknown, some of the prevalences of the following etiologies have been reported. A study reported the incidence of PCEDs or corneal ulcers as 25.4% in patients who received corneal transplantation [7]. Of 250,000 diabetic vitrectomy surgeries per year in the US, 2480–5257 had iatrogenic PCEDs [4,8]. In the US, 20.7 people for every 100,000 people develop PCED secondary to ocular herpes simplex annually [4], and 72% were reported to have corneal–epithelial involvement [9]. Of the 40,000–60,000 cases of herpes zoster ophthalmicus per year, corneal involvement comprises 1600–4800 cases [4]. However, the incidence of PCEDs of the corneal–epithelial involvement is unclear.
1.1. Pathophysiology of PCED
The corneal wound healing process includes a series of events: “migration, proliferation, adhesion and differentiation with cell layer stratification” [10]. Some keratocytes in the stroma go through the initial apoptosis. However, some quiescent keratocytes undergo activation, migrate to the defect [11], and secrete a variety of growth factors essential for effective wound healing [1,5,10,12]. The integrity of the basement membrane is critical for maintaining the fibroblast population. When the basement membrane is damaged or disrupted, corneal epithelial cells secrete TGFβ2 [11], which induces the transformation of fibroblasts to myofibroblasts [11,13]. The regenerated epithelium adheres to the uninjured stroma via hemidesmosomes in a week and up to eight weeks if the stroma is also damaged [5]. When any steps of the described wound healing processes are impeded, the corneal epithelial defect can persist for longer than two weeks and is considered a PCED. PCEDs are primarily caused by abnormalities in epithelial adhesion, limbal stem cell deficiency, inflammation, or neurotrophic pathways.
The epithelium cannot attach to the basement membrane when hemidesmosomes between the two layers are altered. Recurrent corneal erosions, epithelial basement membrane dystrophies, toxic preservatives in eye drop, or corneal degenerative diseases can also interrupt epithelial adhesion [5].
Another common cause of PCEDs is LSCD. Corneal epithelial stem cells promote epithelial regeneration after corneal injury [14]. They reside at the limbus [15], respond to central corneal wounds [15], and migrate centripetally [16].
When inflammatory cascades are activated, the release of cytokines, such as interleukin-1β, tumor necrosis factor α, interleukin-6, interleukin-8; matrix metalloproteinases (MMP); and chemotactic factors is increased for tissue remodeling [2,5]. When the homeostasis of the pro-inflammatory is not maintained, inflammation can be further exaggerated by activated immune cells [2,17]. Consequently, epithelial cells are damaged, compromising the epithelium barrier and hindering regeneration [2]. Patients with systemic inflammatory conditions or autoimmune conditions, such as Stevens–Johnson syndrome, graft-versus-host disease, rosacea, rheumatoid arthritis, Sjögren’s syndrome, etc., are at risk of persistent corneal inflammation [1,5].
PCEDs, as a sequala to neurotrophic damage of the trigeminal nerve, comprise newly categorized neurotrophic keratopathy of stage 3 and above [6]. Recently, the Neurotrophic Keratopathy Study Group has agreed on three main contributing factors to the pathophysiology of NK: altered corneal sensation, decreased trophic factors, and altered lacrimal function unit [6]. The trigeminal nerve, a peripheral nerve, has regenerative capacity [18]. However, when this regenerative ability is compromised, neurotrophic changes can occur. Consequently, the blink reflex, trophic factor release, and tear production are altered. These changes lead to the breakdown of the corneal epithelium, decreased clearance of toxic substances or inflammatory cytokines on the ocular surface, and decreased wound healing from decreased neurotrophic factor releases [6].
1.2. Overview of Diagnostics and Management of PCED
The diagnosis of PCEDs is established clinically. The size of the epithelial defect can be measured under a slit lamp with fluorescein staining, while the depth of the defect can be assessed using anterior segment optical coherence tomography [19]. Slit lamp evaluation helps to identify the presence of infection and the severity of inflammation. Various etiologies of PCEDs should be evaluated. Any abnormalities of the eyelids, blinking, and tear film should be evaluated as all of these can contribute to PCEDs. PCEDs, in the context of NK, can be assessed by measuring the corneal sensitivity. Certain labs can be ordered to evaluate systematic comorbidities such as HbA1C for diabetes, serum retinol-binding protein for vitamin A deficiency, and various antibody panels (anticyclic citrullinated peptide, antinuclear antibody, anti-double-stranded DNA antibody, anti-Ro, and anti-La) for autoimmune diseases [1].
The current non-surgical standard of care for PCEDs includes aggressive lubrication with preservative-free artificial tears, punctal plugs to mechanically maintain lubrication, treatment of underlying conditions, discontinuation of any offending agents, contact lenses, scleral contact lens to protect against mechanical insult, oral tetracyclines to dampen matrix metalloproteinase (MMP) activity, and administration of prophylactic antibiotics and steroids [1,5,20,21,22,23]. Refractory cases to the standard of care can be treated with newer medical management such as autologous serum or platelet-rich plasma tears [24]. PCEDs can be surgically managed with tarsorrhaphy, amniotic membrane transplant (AMT), corneal epithelial stem cell transplantation, and conjunctival flap [2,5,25,26,27,28,29,30].
1.3. Purpose
Timely intervention is imperative to prevent complications associated with unhealed PCEDs, such as increased exposure to infections, corneal scarring, opacification, melting, perforation, and ultimately vision loss [1,31,32]. Research indicates that a longer PCED duration may be a risk factor underlying complications but also a prognostic indicator for requiring extended treatments [31,32]. This review delves into current management strategies and highlights emerging non-surgical and surgical treatment options. Relevant articles were searched with terms such as “persistent epithelial defect”, “persistent corneal epithelial defect”, “neurotropic keratitis”, “neurotropic keratopathy”, “clinical trials”, “emerging treatments”, “surgical managements,” “limbal stem cell deficiency,” “scaffolds”, “cell therapy”, “current surgical management”, and “emerging surgical management” on MEDLINE, PubMed, Google Scholar, ClinicalTrials.gov, International Clinical Trials Registry Platform, and EU Clinical Trials Register.
2. Current PCED Management
2.1. Current Non-Surgical Management
Managing PCEDs involves optimizing the ocular surface to promote effective healing (Table 1). The primary goal of management is to create an environment that supports cellular repair and to minimize the risk of further epithelial breakdown. To effectively treat PCEDs, both the underlying cause and symptoms must be considered. Following identification of the underlying cause, a stepwise system of treatment should be employed, beginning with conservative measures and progressing to more aggressive treatment options if refractory.
Treat the Underlying Cause: The initial step in managing PCEDs is to determine the underlying cause. Addressing the underlying cause is necessary for maximizing the efficacy of subsequent local therapies [24]. For example, PCEDs secondary to autoimmune causes may require treatments that focus on suppressing the inflammatory response, and PCEDs secondary to LSCD may need limbal cell transplant. It is also important to survey for iatrogenic causes. Ophthalmic eye drops that contain preservatives like benzalkonium chloride can damage the integrity of the corneal epithelium [43]. Antibiotics, antivirals, and medications commonly prescribed for glaucoma management are associated with corneal toxicity [21,24].
Aggressive Lubrication: The first line of treatment for PCEDs is aggressive lubrication of the cornea with preservative free artificial tears and ophthalmic ointments [21]. Lubrication supports the healing process by promoting epithelial cell migration, reducing mechanical trauma, and enhancing the stability of the tear film [33].
Punctal Plugs: Punctal plugs are another therapeutic method employed to enhance corneal lubrication and promote healing. By obstructing tear drainage, they increase the retention time of natural tears on the ocular surface, thereby enhancing hydration and supporting the healing process [21]. Since punctal plugs create a reservoir of lubrication, they must be used cautiously when the patient is on the cytotoxic agents in commonly prescribed drops such as antibiotics, antivirals, and glaucoma medications. With the drainage system blocked, the ocular surface is exposed to an increased level of toxins due to prolonged retention. This blockage is particularly concerning in patients chronic ocular surface diseases as their reduced corneal sensitivity may delay the detection of inflammation, potentially exacerbating ocular surface damage [21].
Contact Lens: A bandage or scleral contact lens is also indicated to serve as a protective barrier between the PCED and the environment [20,34]. By providing a physical barrier, lenses allow the epithelial defect to heal without reoffending trauma and irritation. Scleral contact lenses also provide a reservoir of lubrication underneath the lens, further optimizing the corneal surface for healing [2].
Pressure Patching: Pressure patching is an alternative approach to providing a protective barrier to the cornea. Placing two eye pads over the eye and securing them with tape creates a physical barrier, while the added pressure helps prevent lid movement, stabilizes the cornea, and supports epithelial regeneration [44]. However, pressure patching may confer a negative effect by limiting oxygen availability, potentially hindering its regeneration. As a result, its use remains controversial in clinical practice [44,45].
Oral Tetracyclines: Oral tetracyclines taken systemically can effectively treat PCEDs. The anticollagenolytic activities of tetracyclines are due to the resulting inhibition of MMPs involved in the inflammatory process associated with PCEDs [5]. By suppressing MMP activity, tetracyclines can promote healing when there is an inflammatory component to the PCED [35]. However, prolonged usage of oral tetracyclines should be monitored as it has been shown to significantly decrease gut microbiota diversity without recovery post antibiotic withdrawal [36]. Furthermore, broad usage of this antibiotic leads to an increase in the bacterial acquisition of the tetracycline resistance gene tetW among certain strains of the bacterium [36].
Autologous Serum Drops (ASDs): ASDs are created from autologous blood serum. ASDs contains many of the growth factors and nutrients, such as vitamin A and epidermal growth factor, that are present in a healthy tear film yet deficient in the tears of PCED patients [3]. In addition, fibronectin and anti-proteases in ASD are some of the factors in serum believed to promote corneal healing [37]. A case study of a 28-year-old patient reported the effective and complete healing of a two-month-old corneal epithelial defect after 48 h of ASD application six times daily [46]. Platelet-derived therapeutics are discussed under “3. Emerging Non-surgical Management”.
Other Biologics: The REPARO phase I and phase II studies have demonstrated the safety and efficacy of recombinant human nerve growth factor (rh-NGF) eye drops in treating moderate to severe neurotrophic keratitis (NK), a condition where impaired corneal innervation leads to epithelial defects [47,48]. Subsequently, cenegermin (an rh-NGF) received regulatory approval for NK treatment from agencies such as the European Commission, the United States Food and Drug Administration, and other authorities worldwide [38]. Further investigations have supported the role of rh-NGF in managing PCEDs associated with NK. Ref. [39] reported complete healing in all eight patients with moderate NK and PCEDs after an 8-week treatment of six daily drops of cenegermin, with three patients achieving healed PCEDs within 4 weeks [39]. Similarly, ref. [38] demonstrated that cenegermin achieved statistically significant greater reductions in corneal lesion size compared to vehicle-treated controls over an 8-week treatment period [38]. Additionally, cenegermin has shown efficacy when used in conjunction with bandage contact lens. Cheung et al. [6] reported complete resolution of the PCED in 6 out of 10 NK patients and a notable reduction in defect size in three additional eyes at the end of the treatment period [40]. These findings highlight the therapeutic role of cenegermin in addressing PCEDs when neurotrophic dysfunction is a driving factor. Insulin is another biologic that is used for PCED healing. A prospective study reported approximately a 70% reduction in defect size among 23 patients with PCEDs [41]. Similarly, a prospective case series on 10 patients with PCEDs treated with insulin eye drops showed complete re-epithelialization in 82% of the patients [42].
2.2. Current Surgical Management
Surgical management (Table 2) is typically reserved for severe cases that are resistant to other topical treatments. The decision on the priority of the surgical technique totally depends on the underlying disease causing the PCED. Depending on the situation, one or a combination of surgical techniques can be most effective. Surgical management choices will be dependent on the individual patient presentation and medical and surgical history.
Amniotic Membrane Transplant (AMT): The amniotic membrane can promote epithelialization and exhibits anti-inflammatory and anti-scarring properties, making it an effective dressing for various conditions, such as PCEDs with corneal ulceration, acute chemical burns, bullous keratopathy, and LSCD [56]. In an animal study, rabbits with pseudomonas keratitis and PCEDs were treated with AMT, ciprofloxacin, or both [57]. Corneal perforation was present in 85.6% of rabbits in the control group but absent in all treatment groups [57]. The combination of ciprofloxacin and AMT demonstrated the best results in reducing infiltrate size [57]. Additionally, eleven eyes of patients with PCEDs (mean defect area: 13.2 ± 11.3 mm2) underwent AMT, with complete resolution achieved in eight eyes after the initial AMT and in three additional eyes following a second transplantation [58].
Tarsorrhaphy: Tarsorrhaphy is a temporary or permanent procedure to partially or completely close the eyelid for corneal healing. It provides protection against trauma and various exposures. This can be achieved through sutures, botulinum toxin (i.e., to paralyze the upper lid levator muscle), cyanoacrylate glue, or with the addition of a weight (e.g., gold) to the eyelid [59]. In a study of thirty-four eyes with PCEDs of various etiologies, tape splint tarsorrhaphy (TST) achieved complete epithelial defect healing in 85.3% of cases after an average of 22.5 ± 24.3 days, without requiring additional treatment. Best-corrected visual acuity (BCVA) improved from 1.11 ± 0.41 to 0.83 ± 0.70 (p = 0.02). TST is a cost effective and efficient treatment for managing PCEDs [49].
Conjunctival Flap (CF) Surgery: Vascularization of the CF provides the necessary nutrients for corneal wound healing [2], dampens inflammation, and alleviates pain [50]. However, the fine balance required to apply appropriate tension in suturing can add complexity to conventional suturing [50]. CF with fibrin glue instead of conventional sutures showed compatible efficacy results without any conjunctival retraction. All seven patients achieved a stable ocular surface [50]. The use of fibrin glue shortens operation duration and fastens recovery [50]. However, CF is reserved for severe PCEDs because of increased risk of LSCD development, corneal conjunctivalization, neovascularization, and opacification [2,60].
Limbal Stem Cell Transplantation: LSCD is a condition that often leads to PCEDs due to an insufficient number of limbal stem cells in corneal surface repair. Management depends on whether the condition is unilateral or bilateral. For unilateral conditions, a block of the conjunctival–limbal autograft (CLAU) from the intact fellow eye is transplanted onto the affected eye [51]. Another technique to transplant the limbal cells is cultivated limbal epithelial transplantation (CLET), in which cells are expanded ex vivo before transplantation. A study with participants with bilateral LSCD who underwent CLET showed 71.4% of successful construction after four years [52]. Sangwan [53] et al. proposed simple limbal epithelial transplantation (SLET) by combining the benefits of CLAU and CLET. In this technique, an amniotic membrane is transplanted onto the denuded recipient’s ocular surface with the basement membrane side facing up. Subsequently, 8 to 10 small pieces of limbal tissue from a healthy donor are placed and fixed on the amniotic membrane with the epithelial side facing up [52]. Finally, a bandage contact lens is applied to secure the graft [53,61]. The efficacy of SLET was proved in a study in which 95 of 125 eyes (76%) had successful limbal transplant and maintained corneal stability at final visit, which ranged from 1 to 4 years [62].
Keratoplasty: Keratoplasty choice depends on the underlying disease causing the PCED. In both LSCD and neurotrophic conditions, the loss of both limbal stem cells and neuronal support means that simply replacing the cornea does not provide a long-term solution; it only offers short-term improvement [54]. Keratoplasty can be performed either simultaneously with or after limbal reconstruction. A similar challenge arises in neurotrophic conditions, where corneal transplantation alone is insufficient for sustained healing. Neuronal replacement and reconstruction are needed prior to keratoplasty. It serves as a complementary procedure following limbal and neuronal reconstruction or when stromal melting occurs in severe corneal wounds [54]. Mini-conjunctival limbal autograft (CLAU) combined with deep anterior lamellar keratoplasty (DALK) resulted in complete epithelialization and a stable long-term outcome in a patient with total LSCD [63]. Penetrating keratoplasty combined with autologous simple limbal epithelial transplantation (SLET) in severe stromal and surface scarring resulted in a transparent cornea and a visual acuity of 20/100 [60]. In 14 patients who underwent COMET, PKP was performed 7.6 ± 1.3 months later. Over a follow-up period of 28.2 ± 8 months, no recurrence of corneal defects was observed [51]. Keratolimbal allograft (KLAL) combined with central lamellar keratoplasty (CLK) was performed in 13 patients with chronic and severe mustard gas keratopathy (MGK), with a reported success rate of 92.3% over a follow-up period of 87.6 ± 49.8 months [64].
3. Emerging Non-Surgical Management
There are a few emerging medical treatments that are on the rise (Table 3).
3.1. Platelet-Derived Therapeutics
Platelet-rich plasma (PRP) is an emerging treatment modality in regenerative medicine [83]. PRP, which can be further formulated as a platelet gel, has been recognized for its role in tissue repair [65]. To produce PRP, the patient’s blood is anticoagulated with animal-derived thrombin and centrifuged. The PRP layer between the platelet-poor plasma layer and the white/red blood cells layer is aspirated [65,68,70]. PRP is rich in platelet-derived growth factor (PDGF), which is known to be the first responder in cell regeneration and therapeutic angiogenesis [68]. Studies have shown that PRP promotes wound healing in corneal epithelial injury [84] and PCEDs [65,66]. An ongoing clinical trial aims to build upon this potential by studying combination therapies to determine whether supplementing PRP drops with a bandage contact lens, an eye patch with lubricant ointment, or preservative-free lubricant alone produces the quickest healing times for PCEDs [67].
PRP can be formulated not only into topical eyedrops but also clots [69]. Solid-activated PRP, the “clot”, was traditionally applied with a sutured amniotic membrane. Recently, solid-activated PRP is being used in conjunction with a soft contact lens, which is more accessible and cost-effective [85]. This treatment can be effective especially among patients who have contraindications for amniotic membrane usage due to underlying systemic conditions, infections, or ineligibility to be a blood donor [86].
Another platelet-derived treatment modality is platelet-rich in growth factors (PRGF), in which calcium chloride is used as a coagulant instead of animal-derived thrombin [87]. The PRGF production technique avoids collection of the buffy coat and white blood cells [70]. PRGF has a high concentration of growth factors, including not only PDGF but also epithelial growth factor, vascular endothelial growth factor, hepatocyte growth factor, fibroblast growth factor, and nerve growth factor, which aid in the ability of PRGF to improve ocular surface quality [88,89]. In a study involving 20 PCED cases, the application of PRGF eye drops led to complete resolution of the PCED in 17 patients within an average of 10.9 weeks [89].
Additionally, platelet lysate solutions are undergoing development and trials. The process of thermal shocking diluted PRP lyses platelets, which can then be collected as a potential therapeutic solution [70]. In an animal model, platelet lysate was delivered via an ocular wound chamber and was found to be effective in the re-epithelialization of the cornea [71]. In a pilot clinical trial involving 10 patients with PCEDs, 7 patients had a complete resolution of their PCEDs with autologous platelet lysate [72].
3.2. Ocular Bandage Gel (KIO-201)
Hyaluronic acid is a glycosaminoglycan that plays a vital role in the proper function of the cornea. Due to its viscoelastic properties, hyaluronic acid contributes to the structure and plasticity of the cornea [90,91]. Kiora Pharmaceuticals is developing an ocular bandage gel that uses a more stable, cross-linked form of hyaluronic acid called KIO-201 for PCED treatment. In 2023, the completion of an interventional phase 2 study of KIO-201 revealed that five of the eight participants showed an appreciable reduction in the lesion area by the end of the four-week treatment period [73,74].
3.3. Lufeprisen Ophthalmic Gel (AMB-01-006 or NEXPEDE-1)
Amber Ophthalmics is advancing Nexagon (lufepirsen ophthalmic gel), which inhibits the formation of connexin43 gap junction hemichannels. This inhibition has been shown to promote the healing of corneal epithelial defects and vascular recovery [77]. Amber Ophthalmics is currently recruiting for phase 2 and phase 2/3 clinical trials to evaluate its safety and efficacy in PCED management, measuring the proportion of participants that achieve corneal re-epithelialization and maintain re-epithelialization within 28 days [75,76,78].
3.4. The 0.1% RGN-259 Eye Drops
A corneal nerve disorder or damage in NK leads to PCEDs. Stage 2 NK is defined by the presence of a PCED, while Stage 3 NK is characterized by the progression to corneal ulceration, stromal melting, or corneal perforation [92]. Chronic wounds are associated with the overproduction of inflammatory cytokines and chemokines, preventing proper wound healing. Thymosin ß4, an active form of thymosin fraction 5, promotes wound healing by decreasing apoptosis, prevents scarring by decreasing myofibroblasts, strengthens cell-to-cell adhesion by increasing laminin-5 synthesis, and provides oxygen by increasing angiogenesis [93]. In a phase 3 clinical trial, thymosin ß4 was formulated into 0.1% RGN-259 eye drops and administered to 10 patients with PCEDs and stage 2 or 3 NK. Using a five-times-daily dosing schedule, the complete resolution of the PCED occurred in six patients within 28 days [79].
3.5. FGLM-NH2 + SSSR Eye Drops
FGLM-NH2, which is a substance p-derived peptide, and SSSR, which is a derivative from the C-domain of insulin-like growth factor-1, promote epithelial regeneration [80,81]. A combination of FGLM-NH2 and SSSR was applied four times a day for 90 days to 11 patients with NK in the context of leprosy. Of the five patients with PCEDs, all five patients saw a size reduction in their defects, and four patients experienced complete resolution of their PCEDs within 3–14 days of starting the eyedrops [82].
4. Emerging Surgical Management
New studies on surgical management of PCED, including corneal neurotization and cell-based therapies, are under investigation (Table 4).
4.1. Corneal Neurotization
Corneal nerves offer a protective and reparative ecosystem that is essential for optimal corneal healing. Corneal neurotization is a procedure that involves the transplantation of a well-functioning sensory nerve to the damaged cornea [112]. Both direct and indirect corneal neurotization techniques aim to restore corneal innervation. In direct corneal neurotization (DCN), supraorbital or supratrochlear nerves on one side of face are transferred to the other side of face under the nasal bridge [94]. Although DCN can sensitize the cornea, DCN is not applicable to patients with bilateral palsies and leaves extensive scars from bi-coronal incisions [113]. Elbaz et al. developed indirect corneal neurotization, in which the sural nerve graft is used to interconnect the ends of the supraorbital or supratrochlear nerve to the contralateral ocular surface through sub-brow incisions [113].
Nerve ends can be connected in three different ways: end-to-end (ETE), side-to-side (STS), or end-to-side (ETS) [112,114,115,116]. The donor and recipient nerves need to be of a similar size for the ETE approach [117]. However, if there is a significant difference in nerve size or function, the ETS approach may be a more suitable alternative [112]. In a multi-center review, 16 patients with NK who underwent DCN were followed for an average of 31.3 months post-procedure. On average, corneal sensitivity improved from 3.6 mm to 25.3 mm. Additionally, 9 patients demonstrated improved visual acuity, and 11 patients demonstrated an increase in corneal stability [118].
4.2. Cell Therapy-Based Approaches Under Investigation
PCEDs secondary to LSCD require the replenishment of limbal stem cells to promote stem cell migration to the cornea and enhance corneal healing. PCEDs in the context of LSCD may need surgical management [14]. For limbal reconstruction, two essential factors must be considered: an appropriate cell source and the scaffold. For cell replacement, a surface is needed to seed and hold the cells [119]. The amniotic membrane is a well-established biomimetic scaffold used for corneal reconstruction. With its anti-inflammatory and regenerative properties, the amniotic membrane has been used most frequently for cell seeding. Despite its favorable results in culturing various cell types [120,121,122], the amniotic membrane has fallbacks of donor-dependent variations [123] and increased risks of infection and rejection [97]. The following are emerging biomimetic and artificial scaffolds under investigation.
Plywood-like Matrices: Human corneal epithelial cells were cultured on plywood-like matrices for 14 days and were compared with the cells cultured on amniotic membrane [95]. The results proved the compatibility of plywood-like matrices with amniotic membrane with a greater cell amplification [95].
Compressed Collagen Gels: Compressed collagen gels are better suited for corneal limbal epithelial cell expansion than their traditional collagen gel counterparts, which are uncompressed. The compression of these gels allows for stronger attachments between the cells themselves, as well as between the cells and their environment, providing a supportive construct for more morphologically uniform cell growth [96].
Hyaluronan (HA): HA stimulates corneal epithelial migration [98]. Preclinical studies have used HA as scaffolds to expand corneal epithelial stem cells ex vivo [97] and to culture human oral mucosal epithelial cells (OMEC) [124].
Chitosan: Chitosan is a bioresorbable polysaccharide, which is made of chitin, a natural polymer [99]. This is another novel material that may be used as a scaffold for limbal reconstruction. An animal study showed that the alginate–chitosan hydrogel can be successfully used as a scaffold for corneal reconstruction in situ [100].
The source of the cells plays a critical role in corneal healing. In unilateral LSCD, the most favorable option is the use of contralateral autologous limbal stem cells [125]. For bilateral LSCD, allograft limbal stem cells or alternative cell types that have demonstrated potential for differentiation, as listed below, can be utilized for ocular surface healing [126,127,128].
Simple Oral Mucosal Epithelial Transplantation (SOMET): The oral mucosal epithelium is rich in stem cells and can serve as an autologous graft for corneal epithelial restoration [101]. At the 55-month follow-up, 95% of the 17 patients who underwent autologous cultivated oral mucosal epithelial transplantation (COMET) reported improvements in BCVA and corneal scar healing [102]. A newer, simplified approach known as SOMET has since been introduced [103]. Initially performed in a rabbit model, this technique involved securing small rabbit buccal grafts on the cornea with a contact lens. After two weeks, the treatment group had complete resolution of LSCD with signs of ocular surface healing such as reduced neovascularization and decreased fluorescein staining [104]. Additionally, a case report shows the potential efficacy of SOMET in a patient with chronic bilateral ocular sequelae of Stevens–Johnson syndrome. Three weeks after SOMET, the patient’s ocular surface was fully re-epithelialized [103].
MSC is a multipotent cell that can be differentiated into multiple cell types, including osteoblasts, adipocytes, and chondrocytes [129]. MSCs can be acquired from bone marrow, adipose tissue, the umbilical cord, the placenta, and menstrual blood [130]. A systematic review on MSC clinical trials reported that MSCs in research were most frequently derived from bone marrow [105]. MSCs have long been of interest for their ability to secrete anti-inflammatory and antiangiogenic factors [131,132,133,134,135]. In this segment, three different MSC interventions are reviewed: subconjunctival injection of MSCs, MSC transplantation, and MSC secretomes treatment.
MSC Subconjunctival Injection: After establishing the safety of MSCs in animal model corneas [129], a single center, dose-escalation phase I clinical trial was conducted to test the safety of MSCs in patients with PCEDs [136]. The safety of locally delivered MSC via subconjunctival injection was proven without any occurrence of treatment-related toxicity [106]. Some efficacy was demonstrated (Figure 1), with reduced PCED size in five out of eight participants [106,107]. Its efficacy in improving the corneal epithelial barrier is currently under investigation in a multi-center, randomized, double-masked phase II study that started in 2024 [137].
MSC Transplantation: A proof-of-concept clinical trial showed that allogeneic bone marrow-derived MSCT had comparable efficacy to cultivated limbal epithelial transplantation (CLET), with MSCT achieving an 85.7% and CLET achieving an 77.8% success rate at 12 months. Both approaches were deemed effective, safe, and free of adverse effects [108]. In a phase 2a clinical trial, 400,000 adipose tissue-derived adult MSCs were injected into the limboconjunctival quadrant in eight patients and covered by amniotic membrane. Over the 86.5 months follow-up, epithelial defects were resolved in all patients [109]. Other potential cell sources for corneal healing and limbal generation include dental pulp stem cells [127], hair follicle bulge-derived stem cells [128], and epidermal adult stem cells [126]; however, more studies are needed to assess their applicability.
MSC Secretomes: Secretome is defined as “all factors actively or passively released from cells and contains among others soluble proteins (e.g., cytokines, chemokines and growth factors), lipids, free nucleic acids and extracellular vesicles” [138] (p.1). Interestingly, research showed that MSCs’ regenerative and immune-modulatory capabilities are due to paracrine signaling rather than the effects of direct cell transplantation [134,139,140,141]. As a result, akin to MSCs, MSC secretomes and the cultured media have antifibrotic [142], anti-inflammatory [134,143,144], antiangiogenic [114], and regenerative [133,143,145,146] effects. In fact, secretomes have a higher safety profile with low risk of infection, less time needed for expansion, and lower cost in production [147]. Our unmasked, single-center phase 1 clinical trial [110] proved the safety of topical MSC secretomes in low- (two times a day) and medium- (four times a day) dose cohorts. However, in the high-dose group (six times a day), there were two incidences of dose-limiting toxicity. Our preliminary data analysis showed that out of nine participants, seven patients demonstrated improved visual acuity, five patients had an increased corneal sensation, and six patients had fewer self-reported symptoms on the Ocular Surface Disease Index. Kala Pharmaceuticals have also formulated the MSC secretome into a topical ophthalmic solution, and they have named it “KPI-012”. Their phase 1b clinical trial also demonstrated encouraging results. Six out of eight patients showed complete healing of their PCEDs [148]. In early 2023, KPI-012 entered the phase 2 clinical trial phase and received FDA fast track designation, underscoring its potential as a transformative therapy for PCEDs [111]. This randomized, prospective clinical trial is still ongoing, with 47 study sites over the course of eight weeks [119,149].
5. Conclusions
Management of PCEDs can be challenging, especially due to a lack of response to standard care [24]. Delayed treatment of PCEDs increases the likelihood of corneal complications and, ultimately, can lead to vision loss. Researchers propose that patients at risk of recurrent PCEDs can be treated prophylactically and more aggressively in the early stages [24,31,32]. An emphasis on earlier treatments may result in a reduced number of follow-up visits and, consequently, less healthcare expenditure [24]. While the potential prophylactic use of the emerging treatments discussed remains uncertain, promising results from ongoing trials support their viability as treatment options for PCED.
Conceptualization, A.R.D., J.K. and A.M.; methodology, J.K. and A.M.; writing—original draft preparation, J.K., A.M., C.K., Z.B.B., S.S. and A.A.; writing—review and editing, J.K., C.K., A.M. and A.R.D.; visualization, C.K. and J.K.; supervision, A.R.D.; project administration, J.K.; All authors have read and agreed to the published version of the manuscript.
Not applicable.
Not applicable.
No new data were created or analyzed in this study.
Ali Djalilian declares being listed as an inventor on a patent filed by Stanford University which has been licensed to Kala Pharmaceuticals. He has received royalties related to this patent. The authors declare no conflict of interest.
The following abbreviations are used in this manuscript:
| PCED | Persistent Corneal Epithelial Defect |
| LSCD | Limbal Stem Cell Deficiency |
| MMP | Matrix Metalloproteinase |
| AMT | Amniotic Membrane Transplant |
| ASD | Autologous Serum Drops |
| NK | Neurotrophic Keratitis |
| TST | Tape Splint Tarsorrhaphy |
| BCVA | Best-Corrected Visual Acuity |
| CF | Conjunctival Flap |
| CLAU | Conjunctival–limbal Autograft |
| CLET | Cultivated Limbal Epithelial Transplantation |
| PDGF | Platelet-Derived Growth Factor |
| PRGF | Platelet Rich in Growth Factors |
| DCN | Corneal Neuronization |
| OMEC | Oral Mucosal Epithelial Cells |
| SOMET | Simple Oral Mucosal Epithelial Transplantation |
| COMET | Cultivated Oral Mucosal Epithelial Transplantation |
| MSCT | Mesenchymal Stem Cell Transplantation |
| CLET | Cultivated Limbal Epithelial Transplantation |
| BCVA | Best-Corrected Visual Acuity |
| ETE | End-To-End |
| STS | Side-To-Side |
| ETS | End-To-Side |
Footnotes
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Figure 1 Phase I study—safety of locally delivered allogeneic mesenchymal stem cells for promoting corneal repair: (a) PCED size at baseline was 5.7 × 4.4 mm2; (b) complete resolution of PCEDs on Day 90.
Brief descriptions of current non-surgical managements.
| Treatment | Descriptions |
|---|---|
| Treat the Underlying Cause | Address the primary cause like autoimmune disease or LSCD to optimize healing |
| Aggressive Lubrication | Preservative-free artificial tears and ointments that promote epithelial cell migration and improve the tear film stability [ |
| Punctal Plugs | Block tear drainage to enhance hydration, but use cautiously with cytotoxic medications [ |
| Contact Lens (bandage contact lens, scleral lens) | Provides a protective barrier and retains moisture to promote epithelial healing [ |
| Oral Tetracyclines | Reduces inflammation by inhibiting MMPs, but may affect gut microbiota [ |
| Autologous Serum Drops | Blood-derived drops that supply growth factors and nutrients [ |
| Recombinant Human Nerve Growth Factor (rh-NGF) Drops | Cenegermin (a rh-NGF) improves epithelial healing in neurotrophic keratitis-associated PCED [ |
| Insulin Drops | Promotes re-epithelialization and defect closure [ |
Brief descriptions of current surgical managements.
| Treatment | Descriptions |
|---|---|
| Amniotic Membrane Transplant (AMT) | Dressing that promotes epithelialization with anti-inflammatory and anti-scarring properties [ |
| Tarsorrhaphy | Partial or full closure of the eyelid to protect and support healing [ |
| Conjunctival Flap (CF) Surgery | (Reserved for severe PCEDs) Provides vascular support and reduces inflammation and pain [ |
| Limbal Stem Cell Transplantation | Conjunctival–limbal autograft (CLAU) [ |
| Keratoplasty | Replaces damaged corneal tissue, often combined with limbal or neuronal reconstruction [ |
| Stromal Puncture | Enhances epithelial adhesion to the basement membrane and prevents recurrent corneal erosions [ |
Brief descriptions of emerging non-surgical managements.
| Treatment | Study | Descriptions |
|---|---|---|
| Platelet-Derived Therapeutics | Varies | Platelet-rich plasma [ |
| Ocular Bandage Gel | Phase II | Hyaluronic acid crosslinked and stabilized in a bandage gel vehicle [ |
| Lufeprisen | Phase II/III | Ophthalmic gel that inhibits gap junction hemichannels [ |
| 0.1% RGN-259 | Phase III | Thymosin ß4, an active form of thymosin fraction 5, promotes wound healing [ |
| FGLM-NH2 + SSSR | Phase II | FGLM-NH2, a substance p-derived peptide, and SSSR, a derivative from the C-domain of insulin-like growth factor-1, promote epithelial regeneration [ |
Brief descriptions of emerging surgical managements.
| Treatment | Descriptions | |
|---|---|---|
| Corneal Neurotization | Restores corneal innervation using nerve grafts to improve sensation and corneal healing [ | |
| Limbal Cell Reconstruction with Novel Scaffolds | Plywood-like Matrices | Biomimetic scaffold that supports corneal epithelial cell growth with enhanced cell amplification [ |
| Compressed Collagen Gels | Supportive structure for corneal limbal epithelial cell expansion with stronger cell adhesion [ | |
| Hyaluronan (HA) | Stimulates corneal epithelial migration and serves as a scaffold for stem cell expansion [ | |
| Chitosan | A bioresorbable polysaccharide that functions as a scaffold for in situ corneal reconstruction [ | |
| Limbal Cell Reconstruction with Novel Cell Sources | Simple Oral Mucosal Epithelial Transplantation (SOMET) | Autologous graft of oral mucosal epithelial cells for corneal surface restoration [ |
| MSC Interventions | Subconjunctival MSC injection | Ongoing phase 2 clinical trial on subconjunctival injections of human bone marrow-derived MSC [ |
| MSC Transplantation (MSCT) | Mesenchymal stem cells from various sources for ocular surface regeneration [ | |
| MSC Secretomes | Ongoing phase 2 clinical trials on topical ophthalmic solution containing MSC secreted factors [ | |
1. Golhait, P.; Peseyie, R. Persistent Epithelial Defect. StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2024.
2. Thia, Z.Z.; Ho, Y.T.; Shih, K.C.; Tong, L. New Developments in the Management of Persistent Corneal Epithelial Defects. Surv. Ophthalmol.; 2023; 68, pp. 1093-1114. [DOI: https://dx.doi.org/10.1016/j.survophthal.2023.06.001]
3. Tsubota, K.; Goto, E.; Shimmura, S.; Shimazaki, J. Treatment of Persistent Corneal Epithelial Defect by Autologous Serum Application. Ophthalmology; 1999; 106, pp. 1984-1989. [DOI: https://dx.doi.org/10.1016/S0161-6420(99)90412-8]
4. Wirostko, B.; Rafii, M.; Sullivan, D.A.; Morelli, J.; Ding, J. Novel Therapy to Treat Corneal Epithelial Defects: A Hypothesis with Growth Hormone. Ocul. Surf.; 2015; 13, pp. 204-212.e1. [DOI: https://dx.doi.org/10.1016/j.jtos.2014.12.005]
5. Vaidyanathan, U.; Hopping, G.C.; Liu, H.Y.; Somani, A.N.; Ronquillo, Y.C.; Hoopes, P.C.; Moshirfar, M. Persistent Corneal Epithelial Defects: A Review Article. Med. Hypothesis Discov. Innov. Ophthalmol.; 2019; 8, pp. 163-176.
6. Cheung, A.Y.; Holland, E.J.; Lee, W.B.; Beckman, K.A.; Tu, E.; Farid, M.; Pepose, J.; Gupta, P.K.; Fram, N.; Mah, F.
7. Rumelt, S.; Bersudsky, V.; Blum-Hareuveni, T.; Rehany, U. Persistent Epithelial Defects and Ulcers in Repeated Corneal Transplantation: Incidence, Causative Agents, Predisposing Factors and Treatment Outcomes. Graefes Arch. Clin. Exp. Ophthalmol.; 2008; 246, pp. 1139-1145. [DOI: https://dx.doi.org/10.1007/s00417-008-0797-4]
8. Chen, W.-L.; Lin, C.-T.; Ko, P.-S.; Yeh, P.-T.; Kuan, Y.-H.; Hu, F.-R.; Yang, C.-M. In Vivo Confocal Microscopic Findings of Corneal Wound Healing after Corneal Epithelial Debridement in Diabetic Vitrectomy. Ophthalmology; 2009; 116, pp. 1038-1047. [DOI: https://dx.doi.org/10.1016/j.ophtha.2009.01.002]
9. Liesegang, T.J. Epidemiology of Ocular Herpes Simplex. Arch. Ophthalmol.; 1989; 107, pp. 1160-1165.
10. Ljubimov, A.V.; Saghizadeh, M. Progress in Corneal Wound Healing. Prog. Retin. Eye Res.; 2015; 49, pp. 17-45. [DOI: https://dx.doi.org/10.1016/j.preteyeres.2015.07.002]
11. West-Mays, J.A.; Dwivedi, D.J. The Keratocyte: Corneal Stromal Cell with Variable Repair Phenotypes. Int. J. Biochem. Cell Biol.; 2006; 38, pp. 1625-1631. [DOI: https://dx.doi.org/10.1016/j.biocel.2006.03.010]
12. Yu, F.-S.X.; Yin, J.; Xu, K.; Huang, J. Growth Factors and Corneal Epithelial Wound Healing. Brain Res. Bull.; 2010; 81, pp. 229-235. [DOI: https://dx.doi.org/10.1016/j.brainresbull.2009.08.024]
13. Jester, J.V.; Petroll, W.M.; Cavanagh, H.D. Corneal Stromal Wound Healing in Refractive Surgery: The Role of MyoÆbroblasts. Prog. Retin. Eye Res.; 1999; 18, pp. 311-356. [DOI: https://dx.doi.org/10.1016/S1350-9462(98)00021-4]
14. Dua, H.S.; Azuara-Blanco, A. Limbal Stem Cells of the Corneal Epithelium. Surv. Ophthalmol.; 2000; 44, pp. 415-425. [DOI: https://dx.doi.org/10.1016/S0039-6257(00)00109-0]
15. Cotsarelis, G.; Cheng, S.-Z.; Dong, G.; Sun, T.-T.; Lavker, R.M. Existence of Slow-Cycling Limbal Epithelial Basal Cells That Can Be Preferentially Stimulated to Proliferate: Implications on Epithelial Stem Cells. Cell; 1989; 57, pp. 201-209. [DOI: https://dx.doi.org/10.1016/0092-8674(89)90958-6]
16. Dua, H.S.; Forrester, J.V. Clinical Patterns of Corneal Epithelial Wound Healing. Am. J. Ophthalmol.; 1987; 104, pp. 481-489. [DOI: https://dx.doi.org/10.1016/S0002-9394(14)74105-4]
17. Yagci, A.; Gurdal, C. The Role and Treatment of Inflammation in Dry Eye Disease. Int. Ophthalmol.; 2014; 34, pp. 1291-1301. [DOI: https://dx.doi.org/10.1007/s10792-014-9969-x]
18. Mok, E.; Kam, K.W.; Young, A.L. Corneal Nerve Changes in Herpes Zoster Ophthalmicus: A Prospective Longitudinal in Vivo Confocal Microscopy Study. Eye; 2023; 37, pp. 3033-3040. [DOI: https://dx.doi.org/10.1038/s41433-023-02469-0]
19. Konstantopoulos, A.; Kuo, J.; Anderson, D.; Hossain, P. Assessment of the Use of Anterior Segment Optical Coherence Tomography in Microbial Keratitis. Am. J. Ophthalmol.; 2008; 146, pp. 534-542.e2. [DOI: https://dx.doi.org/10.1016/j.ajo.2008.05.030]
20. Blackmore, S.J. The Use of Contact Lenses in the Treatment of Persistent Epithelial Defects. Contact Lens Anterior Eye; 2010; 33, pp. 239-244. [DOI: https://dx.doi.org/10.1016/j.clae.2010.06.004]
21. Jeng, B.H. Treating the Nonhealing Epithelial Defect. Cataract Refract. Surg. Today; 2011; 6, pp. 25-28.
22. Segal, O.; Barkana, Y.; Hourovitz, D.; Behrman, S.; Kamun, Y.; Avni, I.; Zadok, D. Scleral Contact Lenses May Help Where Other Modalities Fail. Cornea; 2003; 22, 308.
23. Perry, H.D.; Kenyon, K.R.; Lamberts, D.W.; Foulks, G.N.; Seedor, J.A.; Golub, L.M. Systemic Tetracycline Hydrochloride as Adjunctive Therapy in the Treatment of Persistent Epithelial Defects. Ophthalmology; 1986; 93, pp. 1320-1322. [DOI: https://dx.doi.org/10.1016/S0161-6420(86)33570-X]
24. Katzman, L.R.; Jeng, B.H. Management Strategies for Persistent Epithelial Defects of the Cornea. Saudi J. Ophthalmol.; 2014; 28, pp. 168-172. [DOI: https://dx.doi.org/10.1016/j.sjopt.2014.06.011]
25. Cosar, C.B.; Cohen, E.J.; Rapuano, C.J.; Maus, M.; Penne, R.P.; Flanagan, J.C.; Laibson, P.R. Tarsorrhaphy: Clinical Experience From a Cornea Practice. Cornea; 2001; 20, pp. 787-791. [DOI: https://dx.doi.org/10.1097/00003226-200111000-00002]
26. Rb, V.; Nr, B. Commentary: Tarsorrhaphy: A Stitch in Time. Indian J. Ophthalmol.; 2020; 68, pp. 33-34.
27. Tseng, S.C.G.; Espana, E.M.; Kawakita, T.; Di Pascuale, M.A.; Li, W.; He, H.; Liu, T.-S.; Cho, T.-H.; Gao, Y.-Y.; Yeh, L.-K.
28. Koizumi, N.; Inatomi, T.; Suzuki, T.; Sotozono, C.; Kinoshita, S. Cultivated Corneal Epithelial Stem Cell Transplantation in Ocular Surface Disorders1. Ophthalmology; 2001; 108, pp. 1569-1574. [DOI: https://dx.doi.org/10.1016/S0161-6420(01)00694-7]
29. Kim, M.S.; Song, S.W.; Kim, J.H.; Woo, H.M. Multifocal Phototherapeutic Keratectomy for the Treatment of Persistent Epithelial Defect. J. Cataract Refract. Surg.; 2000; 26, 1753. [DOI: https://dx.doi.org/10.1016/S0886-3350(00)00640-4]
30. Sejpal, K.; Yu, F.; Aldave, A.J. The Boston Keratoprosthesis in the Management of Corneal Limbal Stem Cell Deficiency. Cornea; 2011; 30, 1187. [DOI: https://dx.doi.org/10.1097/ICO.0b013e3182114467]
31. Jeng, B.H. Abrasions, Planned Defects, and Persistent Epithelial Defects in Corneal Epithelial Wound Healing. JAMA Ophthalmol.; 2016; 134, 1176. [DOI: https://dx.doi.org/10.1001/jamaophthalmol.2016.3086]
32. Jeng, B.H.; Dupps, W.J. Autologous Serum 50% Eyedrops in the Treatment of Persistent Corneal Epithelial Defects. Cornea; 2009; 28, pp. 1104-1108. [DOI: https://dx.doi.org/10.1097/ICO.0b013e3181a2a7f6]
33. Pucker, A.D.; Ng, S.M.; Nichols, J.J. Over the Counter (OTC) Artificial Tear Drops for Dry Eye Syndrome. Cochrane Database Syst. Rev.; 2016; 2016, CD009729. [DOI: https://dx.doi.org/10.1002/14651858.CD009729.pub2]
34. Laurenzi, A. Scleral Lens Applications: A Case Series. Contact Lens Spectr.; 2008; 23, pp. 44-46.
35. Webster, G.; Del Rosso, J.Q. Anti-Inflammatory Activity of Tetracyclines. Dermatol. Clin.; 2007; 25, pp. 133-135. [DOI: https://dx.doi.org/10.1016/j.det.2007.01.012]
36. Moura, I.B.; Grada, A.; Spittal, W.; Clark, E.; Ewin, D.; Altringham, J.; Fumero, E.; Wilcox, M.H.; Buckley, A.M. Profiling the Effects of Systemic Antibiotics for Acne, Including the Narrow-Spectrum Antibiotic Sarecycline, on the Human Gut Microbiota. Front. Microbiol.; 2022; 13, 901911. [DOI: https://dx.doi.org/10.3389/fmicb.2022.901911]
37. Poon, A.C.; Geerling, G.; Dart, J.K.; Fraenkel, G.E.; Daniels, J.T. Autologous Serum Eyedrops for Dry Eyes and Epithelial Defects: Clinical and in Vitro Toxicity Studies. Br. J. Ophthalmol.; 2001; 85, pp. 1188-1197. [DOI: https://dx.doi.org/10.1136/bjo.85.10.1188]
38. Pflugfelder, S.C.; Massaro-Giordano, M.; Perez, V.L.; Hamrah, P.; Deng, S.X.; Espandar, L.; Foster, C.S.; Affeldt, J.; Seedor, J.A.; Afshari, N.A.
39. Roszkowska, A.M.; Inferrera, L.; Aragona, E.; Gargano, R.; Postorino, E.I.; Aragona, P. Clinical and Instrumental Assessment of the Corneal Healing in Moderate and Severe Neurotrophic Keratopathy Treated with Rh-NGF (Cenegermin). Eur. J. Ophthalmol.; 2022; 32, pp. 3402-3410. [DOI: https://dx.doi.org/10.1177/11206721221097584]
40. Cheung, A.Y.; Shah, A.P.; Pierson, K.L.; Denny, M.R.; Nordlund, M.L.; Holland, E.J. Use of Cenegermin in the Presence of Bandage Contact Lenses. Cornea; 2022; 41, pp. 78-82. [DOI: https://dx.doi.org/10.1097/ICO.0000000000002797]
41. Abdi, P.; Ghaffari, R.; Azad, N.; Alshaheeb, A.; Latifi, G.; Soltani Shahgoli, S.; Fakhredin, H. Topical Insulin for Refractory Persistent Corneal Epithelial Defects. Sci. Rep.; 2024; 14, 12459. [DOI: https://dx.doi.org/10.1038/s41598-024-63091-y]
42. Balal, S.; Din, N.; Ashton, C.; Ahmad, S. Healing of Chemical Injury–Related Persistent Corneal Epithelial Defects with Topical Insulin. Cornea; 2023; 42, pp. 1000-1004. [DOI: https://dx.doi.org/10.1097/ICO.0000000000003145] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36729695]
43. Sarkar, J.; Chaudhary, S.; Namavari, A.; Ozturk, O.; Chang, J.-H.; Yco, L.; Sonawane, S.; Khanolkar, V.; Hallak, J.; Jain, S. Corneal Neurotoxicity Due to Topical Benzalkonium Chloride. Investig. Ophthalmol. Vis. Sci.; 2012; 53, pp. 1792-1802. [DOI: https://dx.doi.org/10.1167/iovs.11-8775] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22410563]
44. Campanile, T.M.; St. Clair, D.A.; Benaim, M. The Evaluation of Eye Patching in the Treatment of Traumatic Corneal Epithelial Defects. J. Emerg. Med.; 1997; 15, pp. 769-774. [DOI: https://dx.doi.org/10.1016/S0736-4679(97)00182-0]
45. Easty, D.L. Is An Eye Pad Needed in Cases of Corneal Abrasion?. BMJ; 1993; 307, 1022. [DOI: https://dx.doi.org/10.1136/bmj.307.6911.1022] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/8251774]
46. Akagun, N.; Ozer, P.; Gazyagci, S. Rapid Healing of a Persistent Corneal Epithelial Defect (PCED) with Autologous Serum Treatment. Niger. J. Clin. Pract.; 2020; 23, pp. 123-125. [DOI: https://dx.doi.org/10.4103/njcp.njcp_172_19]
47. Bonini, S.; Lambiase, A.; Rama, P.; Sinigaglia, F.; Allegretti, M.; Chao, W.; Mantelli, F.; Bonini, S.; Lambiase, A.; Rama, P.
48. Bonini, S.; Lambiase, A.; Rama, P.; Filatori, I.; Allegretti, M.; Chao, W.; Mantelli, F.; Bonini, S.; Lambiase, A.; Rama, P.
49. Mimouni, M.; Liu, E.S.; Din, N.; Gouvea, L.; Alshaker, S.; Cohen, E.; Kim, D.B.; Chan, C.C. Tape Splint Tarsorrhaphy for Persistent Corneal Epithelial Defects. Am. J. Ophthalmol.; 2022; 237, pp. 235-240. [DOI: https://dx.doi.org/10.1016/j.ajo.2021.12.006]
50. Chung,; Mehta, J. Fibrin Glue for Gundersen Flap Surgery. Clin. Ophthalmol.; 2013; 7, pp. 479-484. [DOI: https://dx.doi.org/10.2147/OPTH.S42105]
51. Baradaran-Rafii, A.; Heidari-Keshel, S.; Behnaz, N.; Alemzadeh-Ansari, M.; Feizi, S.; Hassanpour, K.; Sadoughi, M.-M.; Filutowski, O.; Ghahari, M. Mini-Conjunctival Limbal Autograft (Mini-CLAU) Using Platelet-Rich Plasma Eye Drops (E-PRP): A Case Series. Cornea; 2023; 42, pp. 1116-1123. [DOI: https://dx.doi.org/10.1097/ICO.0000000000003156]
52. Basu, S.; Fernandez, M.M.; Das, S.; Gaddipati, S.; Vemuganti, G.K.; Sangwan, V.S. Clinical Outcomes of Xeno-Free Allogeneic Cultivated Limbal Epithelial Transplantation for Bilateral Limbal Stem Cell Deficiency. Br. J. Ophthalmol.; 2012; 96, pp. 1504-1509. [DOI: https://dx.doi.org/10.1136/bjophthalmol-2012-301869]
53. Sangwan, V.S.; Basu, S.; MacNeil, S.; Balasubramanian, D. Simple Limbal Epithelial Transplantation (SLET): A Novel Surgical Technique for the Treatment of Unilateral Limbal Stem Cell Deficiency. Br. J. Ophthalmol.; 2012; 96, pp. 931-934. [DOI: https://dx.doi.org/10.1136/bjophthalmol-2011-301164]
54. Dragnea, D.C.; Krolo, I.; Koppen, C.; Faris, C.; Van den Bogerd, B.; Ní Dhubhghaill, S. Corneal Neurotization—Indications, Surgical Techniques and Outcomes. J. Clin. Med.; 2023; 12, 2214. [DOI: https://dx.doi.org/10.3390/jcm12062214]
55. Avni Zauberman, N.; Artornsombudh, P.; Elbaz, U.; Goldich, Y.; Rootman, D.S.; Chan, C.C. Anterior Stromal Puncture for the Treatment of Recurrent Corneal Erosion Syndrome: Patient Clinical Features and Outcomes. Am. J. Ophthalmol.; 2014; 157, pp. 273-279.e1. [DOI: https://dx.doi.org/10.1016/j.ajo.2013.10.005]
56. Meller, D.; Pauklin, M.; Thomasen, H.; Westekemper, H.; Steuhl, K.-P. Amniotic Membrane Transplantation in the Human Eye. Dtsch. Ärztebl. Int.; 2011; 108, pp. 243-248. [DOI: https://dx.doi.org/10.3238/arztebl.2011.0243]
57. Mehdi Soltan Dallal, M.; Nikkhahi, F.; Mostafa Imeni, S.; Molaei, S.; Kazem Hosseini, S.; Kalafi, Z.; Sharifi Yazdi, S.; Molla Agha Mirzaei, H. Amniotic Membrane Transplantation for Persistent Epithelial Defects and Ulceration Due to Pseudomonas Keratitis in a Rabbit Model. J. Ophthalmic Vis. Res.; 2021; 16, pp. 552-557. [DOI: https://dx.doi.org/10.18502/jovr.v16i4.9744]
58. Delbarre, M.; Boucenna, W.; Froussart-Maille, F. Sutureless Lyophilized Amniotic Membrane Grafting for Corneal Epithelial Defects. Eye Contact Lens Sci. Clin. Pract.; 2022; 48, pp. 430-432. [DOI: https://dx.doi.org/10.1097/ICL.0000000000000913]
59. Rajak, S.; Selva, D.; Rajak, J. Performing a Tarsorrhaphy. Community Eye Health; 2015; 28, pp. 10-11.
60. Sharma, A.; Mohan, K.; Sharma, R.; Nirankari, V. Repositioning of Pedicle Conjunctival Flap Performed for Refractory Corneal Ulcer. Middle East Afr. J. Ophthalmol.; 2014; 21, 89. [DOI: https://dx.doi.org/10.4103/0974-9233.124118]
61. Shanbhag, S.; Patel, C.; Goyal, R.; Donthineni, P.; Singh, V.; Basu, S. Simple Limbal Epithelial Transplantation (SLET): Review of Indications, Surgical Technique, Mechanism, Outcomes, Limitations, and Impact. Indian J. Ophthalmol.; 2019; 67, 1265. [DOI: https://dx.doi.org/10.4103/ijo.IJO_117_19]
62. Basu, S.; Sureka, S.P.; Shanbhag, S.S.; Kethiri, A.R.; Singh, V.; Sangwan, V.S. Simple Limbal Epithelial Transplantation. Ophthalmology; 2016; 123, pp. 1000-1010. [DOI: https://dx.doi.org/10.1016/j.ophtha.2015.12.042]
63. Kate, A.; Basu, S. Mini-Conjunctival Autograft Combined with Deep Anterior Lamellar Keratoplasty for Chronic Sequelae of Severe Unilateral Chemical Burn: A Case Report. Int. J. Surg. Case Rep.; 2021; 88, 106508. [DOI: https://dx.doi.org/10.1016/j.ijscr.2021.106508] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34656930]
64. Karimian, F.; Jafarinasab, M.-R.; Feizi, S.; Javadi, M.; Ansari, M.-H.; Hassanpour, K. Long-Term Clinical Outcomes of Keratolimbal Allograft Alone or in Combination with Keratoplasty in Chronic and Delayed-Onset Mustard Gas Keratopathy. Cornea; 2023; 42, 536. [DOI: https://dx.doi.org/10.1097/ICO.0000000000003066] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37000700]
65. Ronci, C.; Ferraro, A.S.; Lanti, A.; Missiroli, F.; Sinopoli, S.; Del Proposto, G.; Cipriani, C.; De Felici, C.; Ricci, F.; Ciotti, M.
66. Özlük, İ.; Yüksel, B.; Küsbeci, T. Comparison of Autologous Serum and Platelet-Rich Plasma in the Treatment of Severe Dry Eye and Persistent Epithelial Defects. Contact Lens Anterior Eye; 2024; 47, 102247. [DOI: https://dx.doi.org/10.1016/j.clae.2024.102247]
67. Mohamed-Noriega, K. Autologous Platelet-Rich Plasma in the Treatment of Persistent Corneal Epithelial Defects. Available online: https://clinicaltrials.gov/study/NCT03653650 (accessed on 13 January 2025).
68. Alio, J.L.; Rodriguez, A.E.; WróbelDudzińska, D. Eye Platelet-Rich Plasma in the Treatment of Ocular Surface Disorders. Curr. Opin. Ophthalmol.; 2015; 26, pp. 325-332. [DOI: https://dx.doi.org/10.1097/ICU.0000000000000169]
69. Alio, J.; Arnalich-Montiel, F.; Rodriguez, A.E. The Role of “Eye Platelet Rich Plasma” (E-Prp) for Wound Healing in Ophthalmology. Curr. Pharm. Biotechnol.; 2012; 13, pp. 1257-1265. [DOI: https://dx.doi.org/10.2174/138920112800624355] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21740369]
70. Giannaccare, G.; Versura, P.; Buzzi, M.; Primavera, L.; Pellegrini, M.; Campos, E.C. Blood Derived Eye Drops for the Treatment of Cornea and Ocular Surface Diseases. Transfus. Apher. Sci.; 2017; 56, pp. 595-604. [DOI: https://dx.doi.org/10.1016/j.transci.2017.07.023]
71. Griffith, G.L.; Holt, A.W.; Eriksson, E.; Johnson, A.J.; McDaniel, J.S. Human Platelet Lysate Delivered via an Ocular Wound Chamber for the Treatment of Corneal Epithelial Injuries. Exp. Eye Res.; 2021; 206, 108493. [DOI: https://dx.doi.org/10.1016/j.exer.2021.108493]
72. Abu-Ameerh, M.A.; Jafar, H.D.; Hasan, M.H.; Al Bdour, M.D.; Msallam, M.; Ababneh, O.H.; Alhattab, D.M.; Al-Kurdi, B.; Awidi, A.A.; Awidi, A.S. Platelet Lysate Promotes Re-Epithelialization of Persistent Epithelial Defects: A Pilot Study. Int. Ophthalmol.; 2019; 39, pp. 1483-1490. [DOI: https://dx.doi.org/10.1007/s10792-018-0968-1]
73. Kiora Pharmaceuticals, Inc. A Pilot Study of the Safety and Effectiveness of the EyeGate Ocular Bandage Gel, a 0.75% Crosslinked Hyaluronic Acid Applied Topically for the Improvement of Persistent Corneal Epithelial Defects (PED). Available online: https://clinicaltrials.gov/study/NCT05436288 (accessed on 14 January 2025).
74. Graue-Hernandez, E.O.; Daniels, E.; Dentiste, A.; Garfias, Y.; Jimenez-Collado, D.; Navas, A.; Arteaga Rivera, J.Y.; Soifer, M.; Chavez Velazquez, D.; Perez, V.L. KIO-201, a Crosslinked, Chemically Modified Form of Hyaluronic Acid, Improves Wound Healing in Patients with Persistent Corneal Epithelial Defects. Investig. Ophthalmol. Vis. Sci.; 2023; 64, 3123.
75. Amber Ophthalmics, Inc. Lufepirsen by Amber Ophthalmics for Persistent Corneal Epithelial Defects: Likelihood of Approval. Pharm. Technol.; 2023; Available online: https://www.pharmaceutical-technology.com/data-insights/lufepirsen-amber-ophthalmics-persistent-corneal-epithelial-defects-likelihood-of-approval/ (accessed on 14 January 2025).
76. Amber Ophthalmics, Inc. A Randomized, Multicenter, Double-Masked, Vehicle-Controlled Phase 2 Study to Evaluate the Safety and Efficacy of NEXAGON®® (Lufepirsen Ophthalmic Gel) in Subjects with Persistent Corneal Epithelial Defects (NEXPEDE-1). Available online: https://clinicaltrials.gov/study/NCT05966493 (accessed on 14 January 2025).
77. Ormonde, S.; Chou, C.-Y.; Goold, L.; Petsoglou, C.; Al-Taie, R.; Sherwin, T.; McGhee, C.N.J.; Green, C.R. Regulation of Connexin43 Gap Junction Protein Triggers Vascular Recovery and Healing in Human Ocular Persistent Epithelial Defect Wounds. J. Membr. Biol.; 2012; 245, pp. 381-388. [DOI: https://dx.doi.org/10.1007/s00232-012-9460-4] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22797940]
78. NEXAGON. Available online: https://www.amberophthalmics.com/nexagon (accessed on 14 January 2025).
79. Sosne, G.; Kleinman, H.K.; Springs, C.; Gross, R.H.; Sung, J.; Kang, S. 0.1% RGN-259 (Thymosin SS4) Ophthalmic Solution Promotes Healing and Improves Comfort in Neurotrophic Keratopathy Patients in a Randomized, Placebo-Controlled, Double-Masked Phase III Clinical Trial. Int. J. Mol. Sci.; 2022; 24, 554. [DOI: https://dx.doi.org/10.3390/ijms24010554] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36613994]
80. Yamada, N.; Harada, D.; Yanai, R.; Morishige, N.; Chikama, T.-I.; Nishida, T. Clinical Efficacy of Eyedrops Containing the Peptides Fglm–Nh2 and Sssr for Treatment of Persistent Corneal Epithelial Defects. Investig. Ophthalmol. Vis. Sci.; 2006; 47, 5018.
81. Yamada, N.; Matsuda, R.; Morishige, N.; Yanai, R.; Chikama, T.-I.; Nishida, T.; Ishimitsu, T.; Kamiya, A. Open Clinical Study of Eye-Drops Containing Tetrapeptides Derived from Substance P and Insulin-like Growth Factor-1 for Treatment of Persistent Corneal Epithelial Defects Associated with Neurotrophic Keratopathy. Br. J. Ophthalmol.; 2008; 92, pp. 896-900. [DOI: https://dx.doi.org/10.1136/bjo.2007.130013]
82. Kondo, S.; Okano, Y.; Iraha, S.; Tokunaga, S. Substance P- and Insulin-like Growth Factor 1-Derived Tetrapeptides for Neurotrophic Keratopathy Related to Leprosy: A Clinical Trial. Ophthalmol. Sci.; 2025; 5, 100634. [DOI: https://dx.doi.org/10.1016/j.xops.2024.100634]
83. Samadi, P.; Sheykhhasan, M.; Khoshinani, H.M. The Use of Platelet-Rich Plasma in Aesthetic and Regenerative Medicine: A Comprehensive Review. Aesthetic Plast. Surg.; 2019; 43, pp. 803-814. [DOI: https://dx.doi.org/10.1007/s00266-018-1293-9]
84. Kamiya, K.; Takahashi, M.; Shoji, N. Effect of Platelet-Rich Plasma on Corneal Epithelial Healing after Phototherapeutic Keratectomy: An Intraindividual Contralateral Randomized Study. BioMed Res. Int.; 2021; 2021, 5752248. [DOI: https://dx.doi.org/10.1155/2021/5752248]
85. Alvarado-Villacorta, R.; Davila-Alquisiras, J.H.; Hernández-Quintela, E.; Ramos-Betancourt, N. Solid Platelet-rich Plasma Combined with Silicone-Hydrogel Soft Contact Lens for Non-Healing Corneal Ulcers: A Case Series. Ocul. Immunol. Inflamm.; 2022; 30, pp. 1123-1128. [DOI: https://dx.doi.org/10.1080/09273948.2020.1871492]
86. García-Lorente, M.; Rodríguez-Calvo-de-Mora, M.; Sánchez-González, J.-M.; Borroni, D.; Zamorano-Martín, F.; Rocha-de-Lossada, C. New Developments in the Management of Persistent Corneal Epithelial Defects. Surv. Ophthalmol.; 2024; 69, pp. 298-299. [DOI: https://dx.doi.org/10.1016/j.survophthal.2023.07.005]
87. Anitua, E. Plasma Rich in Growth Factors: Preliminary Results of Use in the Preparation of Future Sites for Implants. Int. J. Oral Maxillofac. Implant.; 2000; 14, pp. 529-535.
88. Sanchez-Avila, R.M.; Merayo-Lloves, J.; Riestra, A.C.; Anitua, E.; Muruzabal, F.; Orive, G.; Fernández-Vega, L. The Effect of Immunologically Safe Plasma Rich in Growth Factor Eye Drops in Patients with Sjögren Syndrome. J. Ocul. Pharmacol. Ther.; 2017; 33, pp. 391-399. [DOI: https://dx.doi.org/10.1089/jop.2016.0166] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28375790]
89. López-Plandolit, S.; Morales, M.-C.; Freire, V.; Etxebarría, J.; Durán, J.A. Plasma Rich in Growth Factors as a Therapeutic Agent for Persistent Corneal Epithelial Defects. Cornea; 2010; 29, pp. 843-848. [DOI: https://dx.doi.org/10.1097/ICO.0b013e3181a81820]
90. Carlson, E.; Kao, W.W.Y.; Ogundele, A. Impact of Hyaluronic Acid-Containing Artificial Tear Products on Reepithelialization in an In Vivo Corneal Wound Model. J. Ocul. Pharmacol. Ther.; 2018; 34, pp. 360-364. [DOI: https://dx.doi.org/10.1089/jop.2017.0080]
91. Saranraj, P.; Naidu, M.A. Hyaluronic Acid Production and Its Applications—A Review. Int. J. Pharm. Biol. Arch.; 2013; 4, pp. 853-859.
92. Feroze, K.B.; Patel, B.C. Neurotrophic Keratitis. StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2025.
93. Goldstein, A.L.; Kleinman, H.K. Advances in the Basic and Clinical Applications of Thymosin β4. Expert Opin. Biol. Ther.; 2015; 15, pp. 139-145. [DOI: https://dx.doi.org/10.1517/14712598.2015.1011617]
94. Terzis, J.K.; Dryer, M.M.; Bodner, B.I. Corneal Neurotization: A Novel Solution to Neurotrophic Keratopathy. Plast. Reconstr. Surg.; 2009; 123, 112. [DOI: https://dx.doi.org/10.1097/PRS.0b013e3181904d3a] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19116544]
95. Tidu, A.; Ghoubay-Benallaoua, D.; Teulon, C.; Asnacios, S.; Grieve, K.; Portier, F.; Schanne-Klein, M.-C.; Borderie, V.; Mosser, G. Highly Concentrated Collagen Solutions Leading to Transparent Scaffolds of Controlled Three-Dimensional Organizations for Corneal Epithelial Cell Colonization. Biomater. Sci.; 2018; 6, pp. 1492-1502. [DOI: https://dx.doi.org/10.1039/C7BM01163F]
96. Mi, S.; Chen, B.; Wright, B.; Connon, C.J. Plastic Compression of a Collagen Gel Forms a Much Improved Scaffold for Ocular Surface Tissue Engineering over Conventional Collagen Gels. J. Biomed. Mater. Res. A; 2010; 95A, pp. 447-453. [DOI: https://dx.doi.org/10.1002/jbm.a.32861]
97. Chen, D.; Qu, Y.; Hua, X.; Zhang, L.; Liu, Z.; Pflugfelder, S.C.; Li, D.-Q. A Hyaluronan Hydrogel Scaffold-Based Xeno-Free Culture System for Ex Vivo Expansion of Human Corneal Epithelial Stem Cells. Eye; 2017; 31, pp. 962-971. [DOI: https://dx.doi.org/10.1038/eye.2017.8]
98. Nishida, T.; Nakamura, M.; Mishima, H.; Otori, T. Hyaluronan Stimulates Corneal Epithelial Migration. Exp. Eye Res.; 1991; 53, pp. 753-758. [DOI: https://dx.doi.org/10.1016/0014-4835(91)90110-z] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/1783012]
99. Fonseca-Santos, B.; Chorilli, M. An Overview of Carboxymethyl Derivatives of Chitosan: Their Use as Biomaterials and Drug Delivery Systems. Mater. Sci. Eng. C; 2017; 77, pp. 1349-1362. [DOI: https://dx.doi.org/10.1016/j.msec.2017.03.198]
100. Xu, W.; Liu, K.; Li, T.; Zhang, W.; Dong, Y.; Lv, J.; Wang, W.; Sun, J.; Li, M.; Wang, M.
101. Gong, D.; Yan, C.; Yu, F.; Yan, D.; Wu, N.; Chen, L.; Zhang, S.; Fu, Y. Direct Oral Mucosal Epithelial Transplantation Supplies Stem Cells and Promotes Corneal Wound Healing to Treat Refractory Persistent Corneal Epithelial Defects. Exp. Eye Res.; 2022; 215, 108934. [DOI: https://dx.doi.org/10.1016/j.exer.2022.108934]
102. Nakamura, T.; Takeda, K.; Inatomi, T.; Sotozono, C.; Kinoshita, S. Long-Term Results of Autologous Cultivated Oral Mucosal Epithelial Transplantation in the Scar Phase of Severe Ocular Surface Disorders. Br. J. Ophthalmol.; 2011; 95, pp. 942-946. [DOI: https://dx.doi.org/10.1136/bjo.2010.188714]
103. Doctor, M.B.; Rajagopal, R.N.; Basu, S. Simple Oral Mucosal Epithelial Transplantation (SOMET) for Ocular Surface Reconstruction in Stevens-Johnson Syndrome: A Case Report. Int. J. Surg. Case Rep.; 2023; 110, 108643. [DOI: https://dx.doi.org/10.1016/j.ijscr.2023.108643] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37574632]
104. Inamochi, A.; Tomioka, A.; Kitamoto, K.; Miyai, T.; Usui, T.; Aihara, M.; Yamagami, S. Simple Oral Mucosal Epithelial Transplantation in a Rabbit Model. Sci. Rep.; 2019; 9, 18088. [DOI: https://dx.doi.org/10.1038/s41598-019-54571-7]
105. Wang, L.-T.; Ting, C.-H.; Yen, M.-L.; Liu, K.-J.; Sytwu, H.-K.; Wu, K.K.; Yen, B.L. Human Mesenchymal Stem Cells (MSCs) for Treatment towards Immune- and Inflammation-Mediated Diseases: Review of Current Clinical Trials. J. Biomed. Sci.; 2016; 23, 76. [DOI: https://dx.doi.org/10.1186/s12929-016-0289-5]
106. Djalilian, A.; Tu, G.; Abedi, F.; Chang, A.; Soleimani, M.; Araujo, I.; Jung, R.; Kwon, J.; Anwar, K.; Arabpour, Z.
107. Chang, A.Y.; Soleimani, M.; Jung, R.; Tu, G.; Dana, R.; Jeng, B.H.; Hematti, P.; Mahmud, N.; Tu, E.Y.; Joslin, C.E.
108. Calonge, M.; Pérez, I.; Galindo, S.; Nieto-Miguel, T.; López-Paniagua, M.; Fernández, I.; Alberca, M.; García-Sancho, J.; Sánchez, A.; Herreras, J.M. A Proof-of-Concept Clinical Trial Using Mesenchymal Stem Cells for the Treatment of Corneal Epithelial Stem Cell Deficiency. Transl. Res.; 2019; 206, pp. 18-40. [DOI: https://dx.doi.org/10.1016/j.trsl.2018.11.003] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30578758]
109. Boto de los Bueis, A.; Vidal Arranz, C.; Del Hierro-Zarzuelo, A.; Díaz Valle, D.; Méndez Fernández, R.; Gabarrón Hermosilla, M.I.; Benítez del Castillo, J.M.; García-Arranz, M. Long-Term Effects of Adipose-Derived Stem Cells for the Treatment of Bilateral Limbal Stem Cell Deficiency. Curr. Eye Res.; 2024; 49, 345. [DOI: https://dx.doi.org/10.1080/02713683.2023.2297342]
110. Djalilian, A.R. Safety of Topical Mesenchymal Stromal Cell Secretome for Ocular Surface Disease. Available online: https://clinicaltrials.gov/study/NCT05204329; (accessed on 14 January 2025).
111. Kala Pharmaceuticals Receives FDA Fast Track Designation for KPI-012, a Human MSC-S Therapy for Persistent Corneal Epithelial Defect. Available online: https://investors.kalarx.com/news-releases/news-release-details/kala-pharmaceuticals-receives-fda-fast-track-designation-kpi-012/ (accessed on 14 January 2025).
112. Fu, L.; Zeppieri, M. Corneal Neurotization. StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2024.
113. Elbaz, U.; Bains, R.; Zuker, R.M.; Borschel, G.H.; Ali, A. Restoration of Corneal Sensation with Regional Nerve Transfers and Nerve Grafts: A New Approach to a Difficult Problem. JAMA Ophthalmol.; 2014; 132, 1289. [DOI: https://dx.doi.org/10.1001/jamaophthalmol.2014.2316]
114. ESTRADA, R.; LI, N.; SAROJINI, H.; AN, J.; LEE, M.-J.; WANG, E. Secretome From Mesenchymal Stem Cells Induces Angiogenesis Via Cyr61. J. Cell. Physiol.; 2009; 219, pp. 563-571. [DOI: https://dx.doi.org/10.1002/jcp.21701] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19170074]
115. Rönkkö, H.; Göransson, H.; Taskinen, H.-S.; Paavilainen, P.; Vahlberg, T.; Röyttä, M. Comparison of Peripheral Nerve Regeneration with Side-to-Side, End-to-Side, and End-to-End Repairs: An Experimental Study. Plast. Reconstr. Surg. Glob. Open; 2016; 4, e1179. [DOI: https://dx.doi.org/10.1097/GOX.0000000000001179] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28293523]
116. Hendry, J.M.; Alvarez-Veronesi, M.C.; Snyder-Warwick, A.; Gordon, T.; Borschel, G.H. Side-To-Side Nerve Bridges Support Donor Axon Regeneration Into Chronically Denervated Nerves and Are Associated with Characteristic Changes in Schwann Cell Phenotype. Neurosurgery; 2015; 77, 803. [DOI: https://dx.doi.org/10.1227/NEU.0000000000000898]
117. Liu, C.Y.; Arteaga, A.C.; Fung, S.E.; Cortina, M.S.; Leyngold, I.M.; Aakalu, V.K. Corneal neurotization for neurotrophic keratopathy: Review of surgical techniques and outcomes. Ocul. Surf.; 2021; 20, pp. 163-172. [DOI: https://dx.doi.org/10.1016/j.jtos.2021.02.010]
118. Aujla, J.; Tong, J.Y.; Curragh, D.; Caplash, Y.; Chehade, M.; Tumuluri, K.; Au, A.; Low, N.; Avisar, I.; Sagiv, O.
119. Sánchez-Porras, D.; Caro-Magdaleno, M.; González-Gallardo, C.; García-García, Ó.D.; Garzón, I.; Carriel, V.; Campos, F.; Alaminos, M. Generation of a Biomimetic Substitute of the Corneal Limbus Using Decellularized Scaffolds. Pharmaceutics; 2021; 13, 1718. [DOI: https://dx.doi.org/10.3390/pharmaceutics13101718]
120. Jurkunas, U.V.; Yin, J.; Johns, L.K.; Li, S.; Negre, H.; Shaw, K.L.; Samarakoon, L.; Ayala, A.R.; Kheirkhah, A.; Katikireddy, K.
121. Nakamura, T. Transplantation of Cultivated Autologous Oral Mucosal Epithelial Cells in Patients with Severe Ocular Surface Disorders. Br. J. Ophthalmol.; 2004; 88, pp. 1280-1284. [DOI: https://dx.doi.org/10.1136/bjo.2003.038497]
122. Pérez, I.; Galindo, S.; López-Miguel, A.; Nieto-Miguel, T.; De La Mata, A.; López-Paniagua, M.; Alberca, M.; Herreras, J.M.; Calonge, M. In Vivo Confocal Microscopy in Limbal Stem Cell Deficiency After Mesenchymal Stem Cell Transplantation: A Sub-Analysis from a Phase I–II Clinical Trial. Ophthalmol. Ther.; 2023; 12, pp. 3251-3262. [DOI: https://dx.doi.org/10.1007/s40123-023-00809-7]
123. Connon, C.J.; Doutch, J.; Chen, B.; Hopkinson, A.; Mehta, J.S.; Nakamura, T.; Kinoshita, S.; Meek, K.M. The Variation in Transparency of Amniotic Membrane Used in Ocular Surface Regeneration. Br. J. Ophthalmol.; 2010; 94, pp. 1057-1061. [DOI: https://dx.doi.org/10.1136/bjo.2008.153064] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19304581]
124. Yazdani, M.; Shahdadfar, A.; Jackson, C.J.; Utheim, T.P. A Hyaluronan Hydrogel Scaffold for Culture of Human Oral Mucosal Epithelial Cells in Limbal Stem-Cell Therapy. Bioengineering; 2019; 6, 97. [DOI: https://dx.doi.org/10.3390/bioengineering6040097] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31652804]
125. Shanbhag, S.S.; Nikpoor, N.; Rao Donthineni, P.; Singh, V.; Chodosh, J.; Basu, S. Autologous Limbal Stem Cell Transplantation: A Systematic Review of Clinical Outcomes with Different Surgical Techniques. Br. J. Ophthalmol.; 2020; 104, pp. 247-253. [DOI: https://dx.doi.org/10.1136/bjophthalmol-2019-314081]
126. Zhang, P.; Ma, X.; Huang, D.; Yang, X. The Capacity of Goat Epidermal Adult Stem Cells to Reconstruct the Damaged Ocular Surface of Total LSCD and Activate Corneal Genetic Programs. J. Mol. Histol.; 2020; 51, pp. 277-286. [DOI: https://dx.doi.org/10.1007/s10735-020-09879-4] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32388840]
127. Patil, S.; D’Souza, C.; Patil, P.; Patil, V.; Prabhu, M.; Bargale, A.; Kaveeshwar, V.; Kumar, S.; Shetty, P. Culture and Characterization of Human Dental Pulp-derived Stem Cells as Limbal Stem Cells for Corneal Damage Repair. Mol. Med. Rep.; 2019; 20, pp. 4688-4694. [DOI: https://dx.doi.org/10.3892/mmr.2019.10691]
128. Meyer-Blazejewska, E.A.; Call, M.K.; Yamanaka, O.; Liu, H.; Schlötzer-Schrehardt, U.; Kruse, F.E.; Kao, W.W. From Hair to Cornea: Toward the Therapeutic Use of Hair Follicle-Derived Stem Cells in the Treatment of Limbal Stem Cell Deficiency. Stem Cells; 2011; 29, pp. 57-66. [DOI: https://dx.doi.org/10.1002/stem.550]
129. Surico, P.L.; Barone, V.; Singh, R.B.; Coassin, M.; Blanco, T.; Dohlman, T.H.; Basu, S.; Chauhan, S.K.; Dana, R.; Di Zazzo, A. Potential Applications of Mesenchymal Stem Cells in Ocular Surface Immune-Mediated Disorders. Surv. Ophthalmol.; 2024; [DOI: https://dx.doi.org/10.1016/j.survophthal.2024.07.008]
130. Yao, L.; Bai, H. Review: Mesenchymal Stem Cells and Corneal Reconstruction. Mol. Vis.; 2013; 19, pp. 2237-2243.
131. Eslani, M.; Putra, I.; Shen, X.; Hamouie, J.; Afsharkhamseh, N.; Besharat, S.; Rosenblatt, M.I.; Dana, R.; Hematti, P.; Djalilian, A.R. Corneal Mesenchymal Stromal Cells Are Directly Antiangiogenic via PEDF and sFLT-1. Investig. Ophthalmol. Vis. Sci.; 2017; 58, pp. 5507-5517. [DOI: https://dx.doi.org/10.1167/iovs.17-22680] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29075761]
132. Eslani, M.; Putra, I.; Shen, X.; Hamouie, J.; Tadepalli, A.; Anwar, K.N.; Kink, J.A.; Ghassemi, S.; Agnihotri, G.; Reshetylo, S.
133. Fernandes-Cunha, G.M.; Na, K.; Putra, I.; Lee, H.J.; Hull, S.; Cheng, Y.; Blanco, I.J.; Eslani, M.; Djalilian, A.R.; Myung, D. Corneal Wound Healing Effects of Mesenchymal Stem Cell Secretome Delivered Within a Viscoelastic Gel Carrier. Stem Cells Transl. Med.; 2019; 8, pp. 478-489. [DOI: https://dx.doi.org/10.1002/sctm.18-0178] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30644653]
134. Oh, J.Y.; Kim, M.K.; Shin, M.S.; Lee, H.J.; Ko, J.H.; Wee, W.R.; Lee, J.H. The Anti-Inflammatory and Anti-Angiogenic Role of Mesenchymal Stem Cells in Corneal Wound Healing Following Chemical Injury. Stem Cells Dayt. Ohio; 2008; 26, pp. 1047-1055. [DOI: https://dx.doi.org/10.1634/stemcells.2007-0737]
135. Han, Y.; Yang, J.; Fang, J.; Zhou, Y.; Candi, E.; Wang, J.; Hua, D.; Shao, C.; Shi, Y. The Secretion Profile of Mesenchymal Stem Cells and Potential Applications in Treating Human Diseases. Signal Transduct. Target. Ther.; 2022; 7, 92. [DOI: https://dx.doi.org/10.1038/s41392-022-00932-0]
136. Djalilian, A.R. Safety of Locally Delivered Allogeneic Mesenchymal Stromal Cells for Promoting Corneal Repair. Available online: https://clinicaltrials.gov/study/NCT04626583; (accessed on 14 January 2025).
137. Djalilian, A.R. Efficacy of Locally Delivered Allogeneic Mesenchymal Stem Cells for Promoting Corneal Repair. Available online: https://clinicaltrials.gov/study/NCT05705024; (accessed on 14 January 2025).
138. Beer, L.; Mildner, M.; Ankersmit, H.J. Cell Secretome Based Drug Substances in Regenerative Medicine: When Regulatory Affairs Meet Basic Science. Ann. Transl. Med.; 2017; 5, 170. [DOI: https://dx.doi.org/10.21037/atm.2017.03.50] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28480206]
139. Kinnaird, T.; Stabile, E.; Burnett, M.S.; Shou, M.; Lee, C.W.; Barr, S.; Fuchs, S.; Epstein, S.E. Local Delivery of Marrow-Derived Stromal Cells Augments Collateral Perfusion through Paracrine Mechanisms. Circulation; 2004; 109, pp. 1543-1549. [DOI: https://dx.doi.org/10.1161/01.CIR.0000124062.31102.57]
140. Salgado, A.J.; Reis, R.L.; Sousa, N.; Gimble, J.M. Adipose Tissue Derived Stem Cells Secretome: Soluble Factors and Their Roles in Regenerative Medicine. Curr. Stem Cell Res. Ther.; 2010; 5, pp. 103-110. [DOI: https://dx.doi.org/10.2174/157488810791268564]
141. Drago, D.; Cossetti, C.; Iraci, N.; Gaude, E.; Musco, G.; Bachi, A.; Pluchino, S. The Stem Cell Secretome and Its Role in Brain Repair. Biochimie; 2013; 95, pp. 2271-2285. [DOI: https://dx.doi.org/10.1016/j.biochi.2013.06.020]
142. Cargnoni, A.; Ressel, L.; Rossi, D.; Poli, A.; Arienti, D.; Lombardi, G.; Parolini, O. Conditioned Medium from Amniotic Mesenchymal Tissue Cells Reduces Progression of Bleomycin-Induced Lung Fibrosis. Cytotherapy; 2012; 14, pp. 153-161. [DOI: https://dx.doi.org/10.3109/14653249.2011.613930]
143. Bermudez, M.A.; Sendon-Lago, J.; Eiro, N.; Treviño, M.; Gonzalez, F.; Yebra-Pimentel, E.; Giraldez, M.J.; Macia, M.; Lamelas, M.L.; Saa, J.
144. Ma, Y.; Xu, Y.; Xiao, Z.; Yang, W.; Zhang, C.; Song, E.; Du, Y.; Li, L. Reconstruction of Chemically Burned Rat Corneal Surface by Bone Marrow–Derived Human Mesenchymal Stem Cells. Stem Cells; 2006; 24, pp. 315-321. [DOI: https://dx.doi.org/10.1634/stemcells.2005-0046] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16109757]
145. Osugi, M.; Katagiri, W.; Yoshimi, R.; Inukai, T.; Hibi, H.; Ueda, M. Conditioned Media from Mesenchymal Stem Cells Enhanced Bone Regeneration in Rat Calvarial Bone Defects. Tissue Eng. Part A; 2012; 18, pp. 1479-1489. [DOI: https://dx.doi.org/10.1089/ten.tea.2011.0325] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22443121]
146. Lan, Y.; Kodati, S.; Lee, H.S.; Omoto, M.; Jin, Y.; Chauhan, S.K. Kinetics and Function of Mesenchymal Stem Cells in Corneal Injury. Investig. Ophthalmol. Vis. Sci.; 2012; 53, pp. 3638-3644. [DOI: https://dx.doi.org/10.1167/iovs.11-9311]
147. Vizoso, F.J.; Eiro, N.; Cid, S.; Schneider, J.; Perez-Fernandez, R. Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int. J. Mol. Sci.; 2017; 18, 1852. [DOI: https://dx.doi.org/10.3390/ijms18091852]
148. Sanchez-Huerta, V.; Graue-Hernandez, E.O.; Navas, A.; Quiroz-Mercado, H.; Alford, S.; Kharabi, D.; Pflugfelder, S.C. Results of a Phase 1b Clinical Trial of KPI-012, a Novel Secretome Therapy, in Patients with Persistent Corneal Epithelial Defect (PCED). Investig. Ophthalmol. Vis. Sci.; 2022; 63, 3232-A0267.
149. Combangio, Inc. A Study to Evaluate Safety and Efficacy of KPI-012 Ophthalmic Solution in Participants with Persistent Corneal Epithelial Defect (PCED). Available online: https://clinicaltrials.gov/study/NCT05727878 (accessed on 14 January 2025).
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Details
; Kang, Christie 2
; Moghtader Amirhossein 1
; Shahjahan Sumaiya 1 ; Bibak Bejandi Zahra 1 ; Alzein Ahmad 1 ; Djalilian, Ali R 1 1 Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; [email protected] (J.K.); [email protected] (A.M.); [email protected] (S.S.); [email protected] (Z.B.B.); [email protected] (A.A.)
2 Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA; [email protected]