Evaluation of the Clinical Efficacy and Mechanisms of Cord Plasma Eye Drops in the Treatment of Neuropathic Corneal Pain

Neuropathic corneal pain (NCP) is characterized by dysfunctional corneal nerves and ocular symptoms including pain, discomfort, burning, stinging, allodynia, and photophobia, are typically not relieved by conventional dry eye treatment due to its neurobiological nature. NCP can be associated with systemic diseases, such as diabetes mellitus and trigeminal neuralgia, or various ocular conditions such as severe dry eye disease, herpes simplex keratitis, or post-refractive surgery. The incidence of NCP is approximately 11-13% after refractive surgery (unpublished data), and it is likely to increase with the growing prevalence of dry eye and diabetes mellitus, as well as the growing popularity of ocular surgery. Moreover, the symptoms of NCP can greatly impact the quality of life and can cause a significant psychological and economic burden. It is often refractory to conventional treatments, leading to a significant impact on patients' quality of life and present as a challenge for clinicians seeking effective treatment strategies. The limited effectiveness of existing therapies for NCP has prompted the investigation of novel treatment options, including blood-derived eye drops.

Blood-derived eye drops, including serum-derived and plasma-derived eye drops, have been employed in a variety of clinical applications in ocular surface diseases because of their advantageous qualities and ability to enhance the ocular surface. Blood-derived eye drops can be prepared either from patients' own blood, such as autologous serum tears (AST) and Platelet-rich Plasma, or from allogeneic donors such as Umbilical Cord blood serum. A variety of bioactive compounds packed in blood-derived eye drops have equipped them with neuroprotective and regenerative properties that aid in corneal repair and nerve regeneration. Several mechanisms, including neuroprotection, anti-inflammatory effects, control of neuronal sensitization, and promotion of corneal epithelial repair, have been shown.

The potential efficacy of blood-derived eye drops on NCP has previously been studied. Aggarwal et al. have found that AST treatment reduced NCP patients' symptoms and enhanced the recovery of corneal nerve morphology. AST has also been reported to be beneficial for patients with photoallodynia in NCP. With the treatment with 20% AST, patients' allodynia and photoallodynia symptoms significantly improved within 3.6 months. Moreover, using autologous serum has been shown to reduce the appearance of neuromas and sub-basal corneal nerve beading. Additionally, serum tears have been shown to improve corneal nerve total length and number, as well as to reduce neural reflectivity and nerve tortuosity. Aggarwal et al. further found that the quantity of corneal nerve regeneration following treatment with AST correlated with the improvement in patients' symptoms of NCP. Another study investigated the neurotrophic potential of human platelet lysate (HPL) for corneal nerve regeneration in rat models. HPL has significantly higher concentrations of neurotrophic factors compared with human peripheral serum (HPS), and it showed corneal neurotrophic abilities both in vitro and in vivo. Taken together, blood-derived eye drops provide growth factors and cytokines that support corneal nerve regeneration, suppress ocular surface inflammation, and modulate the pain signaling pathways. However, the detailed mechanisms have not been investigated yet. Studies on the clinical efficacy and molecular profiles of the use of cord plasma eye drops in the treatment of NCP are also lacking.

SNEC has collaborated with Singapore Cord Blood Bank to provide cord blood plasma service, and cord blood plasma eye drops have been used as standard clinical care for patients with ocular surface diseases, severe dry eye, and NCP in SNEC. In the pilot study, the size of corneal neuromas has been found to be decreased after 3-month cord plasma eye drops treatment in patients with NCP (please find section 5 for preliminary data). The present proposal aim to evaluate the clinical efficacy and mechanisms of cord plasma eye drops in the treatment of NCP.

Inclusion criteria

• Persistent ocular pain or pain-like symptoms, including burning sensation, allodynia, photoallodynia, stinging, hyperalgesia, throbbing, shooting, sharp, cramping, gnawing, or a feeling of electric shock, with a minimum score of 30% for more than 3 questions in the OPAS questionnaire (see below section for OPAS questionnaire), for at least 3 months;
• Presence of corneal nerve abnormalities, including microneuromas, beading, nerve tortuosity, decreased in corneal nerve fiber density (CNFD) or corneal nerve fiber length (CNFL), on IVCM images;
• Minimal or no ocular surface fluorescein staining, with the National Eye Institute (NEI) and ocular surface Oxford score <2;
• Patients who will receive cord plasma eye drops treatment

Exclusion criteria

• Presence of active ocular surface diseases, such as active infective keratitis, the presence of epithelial defect or any other conditions that may cause nociceptive pain
• Active anterior or posterior blepharitis;
• Presence of concomitant ocular diseases that may cause ocular pain, such as uveitis or other ocular inflammatory diseases;
• Concurrent treatment with immunosuppressants, such as topical cyclosporin or steroid eye drops
• Concurrent use of oral Nonsteroidal anti-inflammatory drugs (NSAID) or other medications that may affect the pain scores