This study aimed to evaluate corneal findings of pterygium cases using in vivo confocal microscopy (IVCM) which is a non-invasive and repeatable method. In this case-control study, 54 patients diagnosed with pterygium and 50 healthy controls were investigated, between 2020 and 2021. After a comprehensive ophthalmological examination, the central corneas of all participants were evaluated by corneal IVCM. Surface epithelial cell, wing cells, basal epithelial cells, nerve fiber density, nerve branch density, anterior and posterior stroma keratocyte densities were measured. Corneas from cases with and without pterygium were similar in terms of age (p = 0.306) and gender (p = 0.564). No statistically significant differences were found in the epithelium cell counts including surface, wing, and basal cells between the two groups (p = 0.950, p = 0.334, and p = 0.624, respectively). No statistically significant differences were observed in subepithelial nerve fiber density (p = 0.849), nerve branch density (p = 0.752), and posterior stromal keratocyte density (p = 0.683) between corneas from cases with and without pterygium. However, corneas from cases with pterygium had significantly higher scores in anterior stromal keratocyte density than those from cases without pterygium (p = 0.045). Corneas from grades 1, 2, and 3 pterygium were similar in cell counts, anterior and posterior stromal keratocyte densities (p > 0.05). However, patients with grade 1 had significantly increased nerve fiber density (p = 0.015) and nerve branch density (p = 0.001) than those with grade 2 and grade 3 pterygium. Corneal IVCM may be useful to better understand the corneal microstructure in cases with pterygium. Comprehensive research on the subject is needed.

To study the association between corneal immune cell dynamics and contact lens (CL) comfort, as well as tear film inflammatory mediators in established CL wearers.

A prospective, cross-sectional study including existing CL wearers was conducted. Symptoms were assessed with a comfort visual analog scale (VAS) and the Contact Lens Dry Eye Questionnaire-8. In-vivo corneal confocal microscopy was used to track immune cell dynamics over 3 timepoints at 5-minute intervals. Trajectory speed was calculated as the total length travelled by cells divided by time; displacement speed as the straight-line distance between the start and end positions of a cell divided by time; and persistence ratio as the ratio of displacement speed and trajectory speed. Measurements were performed for 1-3 cells per participant, and the minimum, maximum, and average values were analyzed. Tear film samples were collected to assess matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1, and the MMP-9/TIMP-1 ratio. Correlations between immune cell dynamics, symptoms, and tear inflammatory mediators, were analyzed.

Nineteen CL wearers (4 men and 15 women) aged 30 ± 5 years were included. Participants wore silicone hydrogel CLs for 8-10 h before clinical assessment. There was a significant association between comfort VAS and the maximum (rho = 0.533; p = 0.019) and average (rho = 0.506; p = 0.027) values of immune cell displacement speed. The concentration of MMP-9 was associated with the minimum value of trajectory speed (rho = 0.621; p = 0.031). Finally, the MMP-9/TIMP-1 ratio was associated with the maximum value of trajectory speed (rho = -0.717; p = 0.030), and the maximum (rho = -0.720; p = 0.008) and average (rho = -0.678; p = 0.015) values of displacement speed.

Corneal immune cell dynamics is related to sensations of discomfort in silicone hydrogel CL wearers, with cell speed possibly being regulated by inflammatory mediators assessed from the tear film. These observations may aid in understanding the mechanisms underlying the discomfort response.

Neuropathic corneal pain (NCP) is an underdiagnosed ocular disorder caused by aberrant nociception and hypersensitivity of corneal nerves, often resulting in chronic pain and discomfort even in the absence of noxious stimuli. Recently, microneuromas (aberrant growth and swelling of the corneal nerve endings) detected using in vivo confocal microscopy (IVCM) have emerged as a promising biomarker for NCP. However, this process is time-intensive and error-prone, limiting its clinical use and availability. In this work, we present a new NCP screening system based on a deep learning model trained to detect microneuromas using a multisite dataset with a combined total of 103,168 IVCM images. Our model showed excellent discriminative ability detecting microneuromas (AuROC: 0.97) and the ability to generalize to data from a new institution (AuROC: 0.90). Additionally, our pipeline provides an uncertainty quantification mechanism that allows it to communicate when its predictions are reliable, further increasing its clinical relevance.

Nociceptors respond to noxious stimuli and transmit pain signals to the central nervous system. In the cornea, the nociceptors located in the most external layer provide a myriad of sensation modalities. Damage to these corneal nerve fibers can induce neuropathic pain. In response, corneal nerves become sensitized to previously non-noxious stimuli. Assessing corneal pain origin is a complex ophthalmic challenge due to variations in its causes and manifestations. Current FDA-approved therapies for corneal nociceptive pain, such as acetaminophen and NSAIDs, provide only broad-acting relief with unwanted side effects, highlighting the need for precision medicine for corneal nociceptive pain. A few targeted treatments, including perfluorohexyloctane (F6H8) eye drops and Optive Plus (TRPV1 antagonist), are FDA-approved, while others are in preclinical development. Treatments that target signaling pathways related to neurotrophic factors, such as nerve growth factors and ion channels, such as the transient receptor potential (TRP) family or tropomyosin receptor kinase A, may provide a potential combinatory therapeutic approach. This review describes the roles of nociceptors in corneal pain. In addition, it evaluates molecules within nociceptor signaling pathways for their potential to serve as targets for efficient therapeutic strategies for corneal nociceptive pain aimed at modulating neurotrophic factors and nociceptive channel sensitivity.

Chronic neuropathic ocular pain (NOP) can develop alongside chronic dry eye (DE) post-laser-assisted in-situ keratomileusis (LASIK), yet its specific characteristics remain poorly understood. This study aims to compare the clinical characteristics of patients who developed both DE and NOP after LASIK to those with only DE and to asymptomatic LASIK patients, to facilitate the diagnosis of NOP.

Prospective, cross-sectional "case-control" comparison study. An 89-subject post-LASIK study comprised 3 groups: 34 patients developing NOP and DE (NOP-DE group), 25 patients developing only DE (DE group), and 30 asymptomatic subjects (control group). Assessments included clinical history and symptom questionnaires (OSDI, mSIDEQ, NRS, WFPRS), anxiety and depression evaluation (HADS), tear film stability (osmolarity and TBUT) and production (Schirmer), and ocular surface integrity. Corneal mechanical and thermal sensitivity thresholds were measured using Belmonte's noncontact esthesiometer, whereas tactile sensitivity threshold was assessed pre-/post-topical anesthesia using the Cochet-Bonnet esthesiometer. In vivo confocal microscopy (IVCM) was used to evaluate the sub-basal nerve plexus characteristics and dendritic cell density in the central cornea. Group comparisons and correlations were conducted.

Compared with DE group, patients in the NOP-DE group exhibited significantly more DE symptoms with mSIDEQ (P = .019) higher level of pain with NRS and WFPRS, increased use of ocular lubrication (P = .003), greater frequency of patients with pathological results on anxiety and depression questionnaires (P < .001), and a higher prevalence of central sensitization syndromes (P < .001). Additionally, NOP-DE patients demonstrated higher tactile corneal sensitivity post-topical anesthesia (P = .002). IVCM revealed lower nerve density (P = .049) and higher microneuroma density (P = .008) in the sub-basal nerve plexus of NOP-DE patients compared to DE patients without NOP (P = .008). Most nerve metrics correlated moderately to strongly with clinical parameters.

Persistent high corneal tactile sensitivity postanesthesia, reduced nerve density, and increased microneuroma density in the central cornea may serve as diagnostic indicators for confirming NOP in patients experiencing chronic DE post-LASIK. These findings underscore the potential utility of incorporating these measures into clinical assessments to improve diagnostic accuracy and guide management strategies in this patient population.

The cornea is the most densely sensory innervated tissue in the body. Sensory corneal nerves are essential to maintain ocular surface homeostasis and are involved in the blink reflex, tear production, and the release of trophic factors that are key in the wound healing process. Compromise of corneal sensory nerves leads to neurotrophic keratopathy (NK), an uncommon degenerative disorder that may lead to corneal epithelial breakdown, ulceration, corneal opacification, and even perforation. Management of this condition is difficult and visual disability often ensues in affected patients. While treatment has been traditionally focused in promoting epithelial healing, the past decade has seen a breakthrough in new medical and surgical therapies geared toward promoting corneal reinnervation. This review presents a comprehensive update on NK, focusing on current as well as potential new strategies for its diagnosis and management.

Postural orthostatic tachycardia syndrome (POTS) is a debilitating condition characterized by autonomic dysregulation. Patients with this disorder may experience orthostatic intolerance, palpitations, fatigue, and a wide variety of other symptoms. The neuropathic symptoms of POTS may be caused by small fiber neuropathy (SFN), which is currently diagnosed using skin nerve biopsy. Corneal confocal microscopy (CCM) is an imaging modality that allows visualization of the corneal nerve layer. Our study aimed to determine whether CCM could detect differences in small nerve fiber parameters between POTS patients with and without signs or symptoms of SFN.

CCM was performed on nine patients, along with a neurological examination. Participants were also asked about neuropathic symptoms by a researcher. Based on examination findings and/or reported symptoms, patients were categorized into SFN+ and SFN- groups for comparison. A chart review was conducted to gather demographic data, medications, autonomic testing results, and medical history, including common POTS comorbidities.

Comparison of nerve fiber parameters using CCM did not reveal a statistically significant difference between the groups. However, valuable insights were gained regarding the logistics of conducting this type of study in POTS patients, including adapting to challenges and improving coordination between the neurology and ophthalmology departments.

CCM may one day replace skin nerve biopsy as a diagnostic tool for SFN in POTS patients. Although this preliminary analysis did not demonstrate significant findings, likely due to the small sample size, we believe CCM may still have a role in POTS research and could eventually become a diagnostic tool used in autonomic clinics.

This study aims to investigate the influence of dendritic cells (DCs) on corneal nerve morphology and the clinical significance in chronic Femtosecond Laser-Assisted Laser in Situ Keratomileusis (FS-LASIK) related dry eye disease (DED).

The cross-sectional study was conducted involving healthy control, DED without FS-LASIK group, and DED after FS-LASIK group. Clinical parameters such as ocular surface disease index (OSDI), fluorescein tear breakup time (FBUT), corneal fluorescein staining (CFS) scores, Schirmer I test (SIt), Cochet-Bonnet esthesiometer (C-BE) were recorded. DCs of in vivo confocal microscopy images were included or excluded during corneal nerve segmentation. Key morphological parameters, including corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), tortuosity, and box-count fractal dimension (Boxdim), were measured. The impact of DCs on nerve metrics and clinical parameters and the correlations between each other were assessed.

The significant reduce in key morphological parameters was observed after eliminating DCs. Significant differences of morphological parameters were observed in DED after FS-LASIK group compared with other two groups. With the increased presence of DCs density in DED especially in DED after FS-LASIK group, the presence of DCs introduced false positives in the correlation analysis of DCs density with corneal morphology in DED after FS-LASIK and in the correlation analysis of corneal morphology with clinical characteristics in DED without FS-LASIK.

The presence of DCs introduces significant biases in the assessments of corneal nerve morphology, primarily false-positive results in DED especially chronic FS-LASIK related DED. Their exclusion improves the precision of nerve measurements, which may enhance the clinical evaluation of corneal nerve morphology. These findings highlight the importance of precise segmentation techniques to minimize DCs related interference in clinical practice.

Transepithelial photorefractive keratectomy using Smart Pulse Technology (SPT-TransPRK) is currently the leading method for superficial refractive surgery, offering advantages such as a non-contact procedure, shorter operation times, and excellent patient cooperation. Laser ablation of the corneal epithelium, Bowman's membrane, and the stroma can effectively correct refractive errors. Thus, the complete healing of the corneal epithelium post-surgery is essential for ensuring good vision. Refractive surgeons should enhance their understanding of corneal wound healing mechanisms and focus on the repair of the corneal epithelium following refractive surgery to ensure the quality of visual health of patients.

A total of five patients experienced varying degrees of delayed corneal epithelial healing following refractive surgery. In Case 1, unhealthy corneal epithelial debris was removed, and ophthalmic ointment was applied to cover the eyes instead of using bandage contact lenses (BCLs) to reconstruct the corneal epithelial barrier. This approach was also successfully implemented in Case 2. Furthermore, amniotic membrane transplantation (AMT) can quickly establish a corneal barrier and promote corneal epithelial regeneration, especially in cases of extensive corneal epithelial detachment. The remaining three patients were suspected of having corneal viral infections based on their medical history and the observation of corneal pathology using a slit lamp microscope. To prevent further infection and promote regeneration, topical steroid drops were discontinued early, and topical antiviral and corneal epithelial regeneration medications were administered alongside systemic antiviral therapy. Steroid drops were resumed after corneal epithelial healing to effectively prevent post-refractive haze.

Delays in corneal epithelial healing after refractive surgery should be taken seriously. BCLs, steroids, and both topical and systemic antiviral therapies should be properly utilized when there is a delay in corneal epithelial healing.

To investigate the geometrical feature of the whorl-like corneal nerve in dry eye disease (DED) across different severity levels and subtypes and preliminarily explore its diagnostic ability.

Cross-sectional study.

The study included 29 healthy subjects (51 eyes) and 62 DED patients (95 eyes).

All subjects underwent comprehensive ophthalmic examinations, dry eye tests, and in vivo confocal microscopy to visualize the whorl-like corneal nerve at the inferior whorl (IW) region and the straight nerve at the central cornea. The structure of the corneal nerve was extracted and characterized using the fractal dimension (CNDf), multifractal dimension (CND0), tortuosity (CNTor), fiber length (CNFL), and numbers of branching points.

The characteristics of quantified whorl-like corneal nerve metrics in different groups of severity and subtype defined by symptoms and signs of DED.

Compared with the healthy controls, the CNDf, CND0, and CNFL of the IW decreased significantly as early as grade 1 DED (P < 0.05), whereas CNTor increased (P < 0.05). These parameters did not change significantly in the straight nerve. As the DED severity increased, CNDf and CNFL in the whorl-like nerve further decreased in grade 3 DED compared with grade 1. Significant nerve fiber loss was observed in aqueous-deficient DED compared with evaporative DED (P < 0.05). Whorl-like nerve metrics correlated with ocular discomfort, tear film break-up time, tear secretion, and corneal fluorescein staining, respectively (P < 0.05). Furthermore, merging parameters of whorl-like and linear nerve showed an area under the curve value of 0.910 in diagnosing DED.

Geometrical parameters of IW could potentially allow optimization of the staging of DED. Reliable and objective measurements for the whorl-like cornea nerve might facilitate patient stratification and diagnosis of DED.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Objectives: Anterior Segment Optical coherence tomography (AS-OCT) can help in the diagnosis and treatment of infectious keratitis, but it has not been studied in cases occurring after corneal refractive surgery procedures such as femtosecond laser in situ keratomileusis (FS-LASIK) and keratorefractive lenticule extraction (KLEx). In these procedures, a surgical interface is created, where infections usually start, thus determining a different AS-OCT pattern compared to non-surgical infections, which begin on the corneal surface. Methods: We retrospectively reviewed 22,756 eyes of 13,564 patients who underwent FS-LASIK and KLEx at our surgical center. Results: Four cases of post-refractive surgery infectious keratitis were included (two after FS-LASIK and two after KLEx), in which the AS-OCT identified an initial infiltrate in the interface, followed by interface inflammation. In one case, after FS-LASIK, interface fluid accumulation occurred. In one case, after KLEx, diffuse interface inflammation led to stromal reabsorption, later compensated by stromal reformation and epithelial hyperplasia, well documented by OCT. Conclusions: AS-OCT represents a useful tool for assessing corneal infections after refractive surgery, guiding the treatment, and evaluating the healing process and residual corneal scarring.

Abnormal corneal nerve function and associated disease is a significant public health concern. It is associated with prevalent ocular surface diseases, including dry eye disease. Corneal nerve dysfunction is also a common side effect of refractive surgeries, as well as a symptom of diseases that cause peripheral neuropathies. Here, we demonstrate in vivo calcium imaging of mouse corneal nerves expressing GCaMP6f, a genetically encoded calcium indicator. A custom fluorescence imaging and stereotactic system was designed, allowing for non-contact imaging of the mouse cornea with an air objective. Dynamic imaging of neuronal activity is demonstrated in the various layers of the cornea and in response to local anesthetic administration. This approach demonstrates a less invasive means of assessing corneal nerve function than has been previously used, and has significant potential for studying the effects of ocular diseases, refractive surgeries, and peripheral neuropathies on corneal nerve function, as well as the effectiveness of various therapies to treat corneal nerve dysfunction.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune neuropathy characterized by progressive or relapsing-remitting weakness and sensory deficits. This study aims to evaluate the utility of corneal confocal microscopy (CCM) in diagnosing and monitoring CIDP.

We analysed 100 CIDP patients and 31 healthy controls using CCM to measure corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Standardized clinical and electroneurographic evaluation were conducted, and statistical analyses were performed to compare CCM parameters between groups and across disease stages.

CIDP patients and subgroups exhibited significant reduction in CNFD, CNFL, and CNBD compared to controls. This reduction was observed in late disease stages and severe overall disability sum score (ODSS), and Inflammatory Neuropathy Cause and Treatment Sensory Sum Score (ISS). CCM parameters correlated with axonal pathology in electroneurography of sensory, but not motor nerves. Despite the significant differences, the diagnostic sensitivity (41%) and specificity (77%) of CCM parameters were limited.

While CCM effectively differentiates CIDP patients from healthy controls and was associated with disease severity, its diagnostic accuracy for routine clinical use is a posteriori. However, CCM shows promise as a non-invasive tool for monitoring sensory axonal pathology in CIDP.

Dry Eye Disease (DED) is a multifactorial condition driven by tear film hyperosmolarity, immune dysregulation, and neuro-immune interactions. The immune system plays a central role in its pathogenesis, influencing both inflammation and ocular surface damage. While traditional immunotherapies like anti-inflammatory agents and immunosuppressants offer symptom relief, their long-term use is limited by side effects. This review focuses on emerging immunotherapies, including biologics, stem cell therapy, gene therapy, nanotechnology, and exosome-based treatments, all of which hold promise in modulating immune responses and promoting tissue repair. The relationship between the ocular microbiome and DED is also explored, with an emphasis on personalized immunotherapy. Key challenges for future research include identifying novel therapeutic targets, optimizing clinical translation, and evaluating the long-term efficacy of these innovative treatments.

Given the crucial role nerves play in maintaining corneal function and integrity, the ability of bioengineered cornea to demonstrate functional nerve regeneration directly influences their longevity and stability. Despite advances in biofabrication techniques and an increasing appreciation of the importance of neural innervation, to this day none have completely replicated the complexity and functionality of the cornea with successful innervation. This review evaluates the materials and fabrication techniques used to produce and enhance innervation in bioengineered cornea. Approaches to facilitating innervation are discussed and methods of assessing innervation compared. Finally, current challenges and future directions for innervated bioengineered cornea are presented, providing guidance for future work. STATEMENT OF SIGNIFICANCE: The functional nerve regeneration in bioengineered corneas directly influences their longevity and stability. Despite advancements in biofabrication techniques and growing recognition of the importance of neural innervation for bioengineered cornea, there remains a lack of comprehensive reviews on this topic. This review addresses the critical gap by evaluating the materials and fabrication techniques employed to promote innervation in bioengineered corneas. Additionally, we discuss various approaches to enhancing innervation, compare assessment methods, and examine both in vitro and in vivo responses. By providing a comprehensive overview of the current state of research and highlighting challenges and future directions, this review aims to provide guidance for inducing innervation of bioengineered cornea.

Keratoconus is a progressive eye disorder primarily affecting individuals in adolescence and early adulthood. The ectatic changes in the cornea cause thinning and cone-like steepening leading to irregular astigmatism and reduced vision. Keratoconus is a complex disorder with a multifaceted aetiology and pathogenesis, including genetic, environmental, biomechanical and cellular factors. Environmental factors, such as eye rubbing, UV light exposure and contact lens wearing, are associated with disease progression. On the cellular level, a complex interplay of hormonal changes, alterations in enzymatic activity that modify extracellular membrane stiffness, and changes in biochemical and biomechanical signalling pathways disrupt collagen cross-linking within the stroma, contributing to structural integrity loss and distortion of normal corneal anatomy. Clinically, keratoconus is diagnosed through clinical examination and corneal imaging. Advanced imaging platforms have improved the detection of keratoconus, facilitating early diagnosis and monitoring of disease progression. Treatment strategies for keratoconus are tailored to disease severity and progression. In early stages, vision correction with glasses or soft contact lenses may suffice. As the condition advances, rigid gas-permeable contact lenses or scleral lenses are prescribed. Corneal cross-linking has emerged as a pivotal treatment aimed at halting the progression of corneal ectasia. In patients with keratoconus with scarring or contact lens intolerance, surgical interventions are performed.

Background: Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder characterized by the formation of intranuclear inclusions in cells. Adult-type NIID usually develops in elderly patients with various clinical manifestations and is sometimes accompanied by ocular symptoms. A case of adult-onset NIID with early and unique manifestations, including a progressive corneal defect and retinal changes, which are concerning at a young age, is reported. Case Presentation: A 29-year-old woman with adult sporadic NIID presented to our department with a progressive corneal disorder. Her neurological symptoms started at the age of 22 years, and she was diagnosed with NIID by skin biopsy and genetic testing. Ocular examination revealed bilateral corneal superficial punctate keratitis, right corneal opacity, decreased vision, nocturnal lagophthalmos, and early retinal changes. Corneal nerve fiber atrophy was detected by in vivo confocal microscopy. With a Cochet-Bonnet aesthesiometer, the progression of NIID and decreased corneal sensation were confirmed. Findings consistent with neurotrophic keratitis and keratoconjunctivitis due to nocturnal lagophthalmos were both suggested as being complications of her underlying NIID. Treatment with punctal plugs, sodium hyaluronate eye drops, diquafosol sodium eye drops, systemic and local antivirals, and local steroid medications resulted in the gradual improvement in the irregularity and opacity of the epithelium. Conclusions: NIID may lead to neurotrophic keratopathy due to impairment of the corneal sensory nerves. Nocturnal lagophthalmos is a remarkable finding in a case of NIID. The findings in the present case highlight the complex and multifaceted nature of NIID, with neurological and ocular manifestations requiring a multidisciplinary approach to management.

The purpose of this study was to delineate the concurrence of limbal stem cell deficiency (LSCD) and neurotrophic keratopathy in patients with ocular graft-vs-host disease (oGVHD).

Medical records of patients with oGVHD were reviewed. Parameters collected included corneal sensitivity measured by using a noncontact esthesiometer, corneal fluorescein staining score (National Eye Institute grading scale), tear volume (Schirmer I test), and subbasal nerve density and limbal structure assessed by in vivo confocal microscopy.

Twenty-eight patients (mean age: 60.8 ± 10.4 years) with oGVHD were included; 50% (n = 14) had partial LSCD (P-LSCD), and 32% (n = 9) had complete LSCD (C-LSCD). Patients with C-LSCD showed significantly reduced total nerve density and branch nerve density compared with those with P-LSCD ( P < 0.02, P < 0.04) and no LSCD ( P < 0.01, P = 0.02). Dendritic cell density was significantly higher in the C-LSCD group compared with the no LSCD group ( P < 0.05). Corneal sensitivity was significantly reduced in patients with C-LSCD compared with those with P-LSCD ( P = 0.01) and no LSCD ( P < 0.02). Patients with C-LCSD had higher corneal fluorescein staining scores than patients with P-LSCD ( P < 0.01) and no LSCD ( P = 0.02).

This study highlights a significant concurrence of LSCD and neurotrophic keratopathy in patients with oGVHD, underscoring the link between inflammation, neurodegeneration, and loss of stem cell function.

To establish an automated corneal nerve analysis system for corneal in vivo confocal microscopy (IVCM) images from both the whorl-like corneal nerves in the inferior whorl (IW) region and the straight ones in the central cornea and to characterise the geometric features of cornea nerves in dry eye disease (DED).

An encoder-decoder-based semi-supervised method was proposed for corneal nerve segmentation. This model's performance was compared with the ground truth provided by experienced clinicians, using Dice similarity coefficient (DSC), mean intersection over union (mIoU), accuracy (Acc), sensitivity (Sen) and specificity (Spe). The corneal nerve total length (CNFL), tortuosity (CNTor), fractal dimension (CNDf) and number of branching points (CNBP) were used for further analysis in an independent DED dataset including 50 patients with DED and 30 healthy controls.

The model achieved 95.72% Acc, 97.88% Spe, 80.61% Sen, 75.26% DSC, 77.57% mIoU and an area under the curve value of 0.98. For clinical evaluation, the CNFL, CNBP and CNDf for whorl-like and straight nerves showed a significant decrease in DED patients compared with healthy controls (p<0.05). Additionally, significantly elevated CNTor was detected in the IW in DED patients (p<0.05). The CNTor for straight corneal nerves, however, showed no significant alteration in DED patients (p>0.05).

The proposed method segments both whorl-like and straight corneal nerves in IVCM images with high accuracy and offered parameters to objectively quantify DED-induced corneal nerve injury. The IW is an effective region to detect alterations of multiple geometric indices in DED patients.

To evaluate and compare subbasal corneal nerve parameters of the inferior whorl in patients with dry eye disease (DED), neuropathic corneal pain (NCP), and controls using a novel deep-learning-based algorithm to analyze in-vivo confocal microscopy (IVCM) images.

Subbasal nerve plexus (SNP) images of the inferior whorl of patients with DED (n = 49, 77 eyes), NCP (n = 14, 24 eyes), and controls (n = 41, 59 eyes) were taken with IVCM and further analyzed using an open-source artificial intelligence (AI)-based algorithm previously developed by our group. This algorithm automatically segments nerves, immune cells, and neuromas in the SNP. The following parameters were compared between groups: nerve area density, average nerve thickness, average nerve segment tortuosity, junction point density, neuroma density, and immune cell density.

160 eyes of 104 patients (63 % females), aged 56.8 ± 15.4 years, were included. The mean nerve area density was significantly lower in the DED (P = 0.012) and NCP (P < 0.001) groups compared to the control group. The junction point density was lower in the NCP group compared with control (P = 0.001) and DED (P = 0.004) groups. The immune cell density was higher in the DED group compared with controls (P < 0.001).

Deep-learning-based analysis of IVCM images of the corneal SNP inferior whorl distinguished a decreased mean nerve area density in patients with DED and NCP compared with controls and an increased immune cell density in patients with oGVHD- and SS-associated DED. These findings suggest that the inferior whorl could be used as landmark to distinguish between patients with DED and NCP.

Ocular surface disorders (OSDs) are a prevalent and often debilitating condition encountered in clinical practice, particularly by allergists and clinical immunologists.

A comprehensive guide to office procedures for evaluating and managing OSDs, with a specific focus on ocular allergies, would assist in the evaluation process that begins with an initial patient assessment utilizing standardized forms to systematically gather detailed medical history, symptomatology, and environmental exposure data. This structured approach ensures a thorough understanding of the patient's condition and facilitates targeted interventions. In addition to allergy testing, the assessment of the tear film is essential for a comprehensive evaluation of OSDs. The Schirmer test is employed to quantify tear production, providing objective data on tear film adequacy and guiding interventions for tear film deficiencies.

This multifaceted diagnostic approach ensures that all contributing factors to OSDs are identified and appropriately managed. By integrating these office procedures, allergists and clinical immunologists can enhance their diagnostic accuracy and therapeutic efficacy, ultimately improving patient outcomes. This manuscript provides a practical resource, outlining some of the methodologies and clinical applications of each procedure, and highlighting their role in the holistic management of OSDs in allergic patients.

This study aimed to comprehensively explore the intricacies of corneal neurotization (CN) and the nuanced factors that set it apart from routine clinical practice, exerting a substantial influence on its success. A symbiotic relationship is evident between corneal innervation and ocular surface health. The loss of corneal innervation results in a potentially challenging corneal condition known as neurotrophic keratopathy (NK). The majority of treatments are primarily focused on preventing epithelial breakdown rather than addressing the underlying pathogenesis. Consequently, to address the impaired corneal sensation (underlying etiology), a novel surgical approach has emerged, namely CN, which involves transferring healthy sensory nerve axons to the affected cornea. This review offers valuable insights into the existing body of supporting evidence for CN, meticulously examining clinical studies, case reports, and experimental findings. The aim is to enhance our understanding of the effectiveness and potential outcomes associated with this innovative surgical technique. The exploration of innovative therapeutic avenues holds promise for revolutionizing the management of NK, offering a potentially permanent solution to a condition once deemed incurable and severely debilitating.

To investigate the tear proteomic and neuromediator profiles, in vivo confocal microscopy (IVCM) imaging features, and clinical manifestations in neuropathic corneal pain (NCP) patients.

Cross-sectional study.

A total of 20 NCP patients and 20 age-matched controls were recruited. All subjects were evaluated by corneal sensitivity, Schirmer test, tear break-up time, and corneal and ocular surface staining, Ocular Surface Disease Index and Ocular Pain Assessment Survey questionnaires were administered, as well as IVCM examinations for corneal nerves, microneruomas, and epithelial and dendritic cells. Tears were collected for neuromediator and proteomic analysis using enzyme-linked immunosorbent assay and data-independent acquisition mass spectrometry.

Burning and sensitivity to light were the 2 most common symptoms in NCP. A total of 188 significantly dysregulated proteins, such as elevated metallothionein-2, creatine kinases B-type, vesicle-associated membrane protein 2, neurofilament light polypeptide, and myelin basic protein, were identified in the NCP patients. The top 10 dysregulated biological pathways in NCP include neurotoxicity, axonal signaling, wound healing, neutrophil degradation, apoptosis, thrombin signaling mitochondrial dysfunction, and RHOGDI and P70S6K signaling pathways. Compared to controls, the NCP cohort presented with significantly decreased corneal sensitivity (P < .001), decreased corneal nerve fiber length (P = .003), corneal nerve fiber density (P = .006), and nerve fiber fractal dimension (P = .033), as well as increased corneal nerve fiber width (P = .002), increased length, total area and perimeter of microneuromas (P < .001, P < .001, P = .019), smaller corneal epithelial size (P = .017), and higher nerve growth factor level in tears (P = .006).

These clinical manifestations, imaging features, and molecular characterizations would contribute to the diagnostics and potential therapeutic targets for NCP.

The purpose of this study was to report the outcomes of a novel artificial endothelial replacement membrane implant for treating corneal edema after failed repeat endothelial keratoplasty (EK).

This was a retrospective interventional case series.

Patients with chronic corneal edema underwent removal of the EK graft and implantation of an artificial endothelial replacement membrane (EndoArt, EyeYon Medical, Israel) several months after 2 or more Descemet stripping endothelial keratoplasty procedures. The implant was secured to the posterior corneal surface using an air-gas bubble. Outcome measures included corrected distance visual acuity (logMAR), central corneal thickness, device-related complications, and ocular discomfort.

Five eyes of 5 patients underwent EndoArt implantation. Six months after surgery, the synthetic endothelial replacement membrane was well-centered and adherent to the posterior corneal surface, with improvement in central corneal transparency in all patients. Corrected distance visual acuity increased from mean 1.26 ± 0.25 (logMAR) preoperatively to 0.74 ± 0.44 (logMAR) postoperatively ( P = 0.06). Central corneal thickness significantly decreased from a mean of 805 ± 135 μm (excluding the EK graft) preoperatively to 588 ± 60 μm (excluding the EndoArt) postoperatively ( P = 0.015). No severe device-related complications developed after surgery, although most patients required more than 1 air-gas bubble injection to achieve complete implant adhesion. All patients experienced preoperative reduction in subjective ocular pain.

Synthetic endothelial replacement membrane implantation improves central corneal transparency and visual acuity in patients with failed EK and guarded prognosis for repeat keratoplasty. No significant implant-related adverse events occurred after surgery.

The purpose of this study was to determine the association between corneal images provided by in vivo confocal microscopy (IVCM) with clinical parameters and conjunctival expression of HLA-DR antigen in patients with dry eye disease (DED).

Two hundred fourteen eyes of 214 patients with DED were analyzed, consisting of 2 groups of patients - 63 with autoimmune dry eye disease (AIDED) and 151 with non-autoimmune dry eye disease (NAIDED). Patients underwent a full clinical examination, including symptom screening, using the Ocular Surface Disease Index (OSDI) questionnaire, and objective analysis of DED signs by Schirmer's testing, tear break-up time (TBUT), Oxford's test, and IVCM corneal imaging. The IVCM scoring criteria were based on corneal sub-basal nerve density (ND), nerve morphology (NM), and inflammatory cell (IC) density. Quantification of conjunctival HLA-DR antigen was performed by flow cytometry.

The total IVCM score (T-IVCM) as well as the IVCM-IC subscore (sc) were positively correlated with HLA-DR levels with r = 0.3, P < 0.001 and r = 0.3, P < 0.01, respectively in the total population of patients with DED. The IVCM-NDsc was negatively correlated with TBUT in patients with AIDED (r = -0.2, P < 0.05) and with the Schirmer's test in patients with NAIDED (r = -0.24, P < 0.05). However, the IVCM-NMsc was positively correlated with the Oxford score only in patients with AIDED (r = 0.3, P < 0.05).

The proposed IVCM scoring system showed significant correlations with clinical parameters along with conjunctival HLA-DR quantification in patients with DED.

The IVCM grading score represents an interesting point of commonality among clinical parameters, imaging, and molecular investigation of the ocular surface.

Transthyretin-related amyloidosis (ATTRv) is a progressive multisystem disorder, predominantly involving the peripheral nerve system (PNS) and heart. Quantification of small fiber damage may help guide treatment decisions, as amyloid deposits frequently affect those fibers early in disease course. Corneal confocal microscopy (CCM) is a promising method to monitor patients with ATTRv, due to similarities between corneal nerves and PNS, as the cornea is innervated by Aδ and C fibers.

We compared CCM measures from ATTRv patients to a group of healthy individuals, matched by age and gender. We then investigated the correlations between small fiber tests (SFT): CCM, LDI-Flare and CDT, COMPASS-31 and disability scales (RODS and ONLS) in patients.

Of 20 patients (6 with V30M), mean age 50.3±15.3Y, 7 female (35%), six (30%) had polyneuropathy and 10 (50%) carpal tunnel syndrome. CDT was abnormal in 9 and LDI-flare in 6 patients. CCM was abnormal in 19 tested patients and significantly reduced when compared to controls (CNFL: 6.31±0.31 vs. 15.21±1.02mm/mm2, p<0.001). Mean COMPASS-31-scores were 22.27±22.84; RODS and ONLS were 38.15±12.33 and 2.05±2.3, with no significant differences between sub-group scores. Disease duration was significantly correlated with ONLS (0.43, p=0.05) and RODS (0.46, p=0.03). There were no significant correlations between measures of disability and SFT.

In a diverse cohort of ATTRv patients, CCM was the most frequent abnormal measurement. CCM can be a useful test to triage patients in the early disease stages and with few or equivocal symptoms.

To compare, between Alzheimer's disease (AD) patients and healthy individuals, corneal subbasal nerve plexus (CSNP) parameters and corneal sensitivities.

Twenty-two patients who were followed up with Alzheimer's disease (Alzheimer's group) and 18 age- and gender-matched healthy individuals (control group) were included in this cross-sectional study. CSNP parameters, including nerve fiber length (NFL), nerve fiber density (NFD), and nerve branch density (NBD), were evaluated using in vivo confocal microscopy. Corneal sensitivity was evaluated using a Cochet-Bonnet esthesiometer. The results were compared between the two groups.

In the Alzheimer's group, NFL was 12.2 (2.4) mm/mm2, NFD was 12.5 [3.1] fibers/mm2, and NBD was 29.7 [9.37] branches/mm2. In the control group, NFL was 16.5 (2.0) mm/mm2, NFD was 25.0 [3.13] fibers/mm2, and NBD was 37.5 [10.9] branches/mm2. All three parameters were significantly lower in the Alzheimer's group compared to the control group (p < 0.001, p < 0.001, and p = 0.001, respectively). Similarly, corneal sensitivity was significantly lower in the Alzheimer's group (55.0 [5.0] mm) compared to the control group (60.0 [5.0] mm) (p < 0.001).

We determined that, in AD, corneal sensitivity decreases significantly, in parallel with the decrease in corneal nerves. Changes in the corneal nerve plexus and a decrease in corneal sensitivity may be used in the early diagnosis and follow-up of AD. In addition, ocular surface problems secondary to these changes should also be kept in mind.

Corneal nerves and dendritic cells are increasingly being visualised to serve as clinical parameters in the diagnosis of ocular surface diseases using intravital confocal microscopy. In this review, different methods of image analysis are presented. The use of deep learning algorithms, which enable automated pattern recognition, is explained in detail using our own developments and compared with other established methods.

(1) Background: Neurologic and musculoskeletal diseases represent a considerable portion of the underlying etiologies responsible for the widely prevalent symptoms of pain, weakness, numbness, and paresthesia. Because of the subjective and often nonspecific nature of these symptoms, different diagnostic modalities have been explored and utilized. (2) Methods: Literature review. (3) Results: Nerve and muscle biopsy remains the gold standard for diagnosing many of the responsible neurological and musculoskeletal conditions. However, the need for invasive tissue sampling is diminishing as more investigations explore alternative diagnostic modalities. Because of this, it is important to explore the current role of neurosurgical intervention for nerve and muscle biopsies and its current relevance in the diagnostic landscape of neurological and musculoskeletal disorders. With consideration of the role of nerve and muscle biopsy, it is also important to explore innovations and emerging techniques for conducting these procedures. This review explores the indications and emerging techniques for neurological intervention for nerve and muscle biopsies. (4) Conclusions: The role of neurosurgical intervention for nerve and muscle biopsy remains relevant in diagnosing many neurological and musculoskeletal disorders. Biopsy is especially relevant as a supportive point of evidence for diagnosis in atypical cases. Additionally, emerging techniques have been explored to guide diagnostics and biopsy, conduct less invasive biopsies, and reduce risks of worsening neurologic function and other symptoms secondary to biopsy.

Laser therapy has been proven as an effective technique for managing ophthalmological disorders. To guide future research, we conducted a bibliometric analysis of laser applications in eye diseases from 1990 to 2022, aiming to identify key themes and trends.

We retrieved 3027 publications from the Web of Science Core Collection (WoSCC). Bibliometrix was used for science mapping of the literature, while VOSviewer and CiteSpace were applied to visualize co-authorship, co-citation, co-occurrence, and bibliographic coupling networks.

From a co-citation reference network, we identified 52 distinct clusters. Our analysis uncovered three main research trends. The first trend revolves around the potential evolution of corneal laser surgery techniques, shifting from the treatment of refractive errors to broader applications in biomedical optics. The second trend illustrates the advancement of laser applications in treating a range of disorders, from retinal and ocular surface diseases to glaucoma. The third trend focuses on the innovative uses of established technologies.

This study offers significant insights into the evolution of laser applications in ophthalmology over the past 30 years, which will undoubtedly assist scientists in directing further research in this promising field.

Corneal nerve impairment contributes significantly to dry eye disease (DED) symptoms and is thought to be secondary to corneal epithelial damage. Transient receptor potential vanilloid-1 (TRPV1) channels abound in corneal nerve fibers and respond to inflammation-derived ligands, which increase in DED. TRPV1 overactivation promotes axonal degeneration in vitro, but whether it participates in DED-associated corneal nerve dysfunction is unknown. To explore this, DED was surgically induced in wild-type and TRPV1-knockout mice, which developed comparable corneal epithelial damage and reduced tear secretion. However, corneal mechanosensitivity decreased progressively only in wild-type DED mice. Sensitivity to capsaicin (TRPV1 agonist) increased in wild-type DED mice, and consistently, only this strain displayed DED-induced pain signs. Wild-type DED mice exhibited nerve degeneration throughout the corneal epithelium, whereas TRPV1-knockout DED mice only developed a reduction in the most superficial nerve endings that failed to propagate to the deeper subbasal corneal nerves. Pharmacologic TRPV1 blockade reproduced these findings in wild-type DED mice, whereas CD4+ T cells from both strains were equally pathogenic when transferred, ruling out a T-cell-mediated effect of TRPV1 deficiency. These data show that ocular desiccation triggers superficial corneal nerve damage in DED, but proximal propagation of axonal degeneration requires TRPV1 expression. Local inflammation sensitized TRPV1 channels, which increased ocular pain. Thus, ocular TRPV1 overactivation drives DED-associated corneal nerve impairment.

Background: We evaluate the relationship between corneal nerve structure and function in a veteran population. Methods: 83 veterans (mean age: 55 ± 5 years) seen at the Miami Veterans Affairs (VA) eye clinic were included in this study. Each individual filled out questionnaires to evaluate ocular symptoms (5-Item Dry Eye Questionnaire, DEQ5; Ocular Surface Disease Index, OSDI) and ocular pain (Numerical Rating Scale, NRS; Neuropathic Pain Symptom Inventory modified for the Eye, NPSI-Eye). The individuals also underwent an ocular surface examination that captured functional nerve tests including corneal sensation, corneal staining, and the Schirmer test for tear production. Corneal sub-basal nerve analysis was conducted using in vivo confocal microscopy (IVCM) images with corneal nerve density, length, area, width, and fractal dimension captured. IVCM and functional corneal metrics from the right eye were examined using correlational and linear regression analysis. Results: Most corneal structural metrics were not related to functional metrics, except for weak correlations between various IVCM metrics and tear production. In addition, corneal nerve fiber area was positively related to corneal sensation (r = 0.3, p = 0.01). On linear regression analyses, only the corneal fractal dimension remained significantly related to tear production (β = -0.26, p = 0.02) and only the corneal nerve fiber area remained significantly related to corneal sensation (β = 0.3, p = 0.01). Conclusions: Most corneal nerve structural metrics did not relate to functional metrics in our veteran population, apart from a few weak correlations between structural metrics and tear production. This suggests that using corneal nerve anatomy alone may be insufficient for predicting corneal function.

The corneal cap thickness is a vital parameter designed in small incision lenticule extraction (SMILE). The purpose was to investigate the changes in corneal subbasal nerve plexus (SNP) and stromal cells with different cap thicknesses and evaluate the optimized design for the surgery.

In this prospective, comparative, non-randomized study, a total of 108 eyes of 54 patients who underwent SMILE were allocated into three groups with different corneal cap thicknesses (110 μm, 120 μm or 130 μm group). The SNP and stromal cell morphological changes obtained from in vivo corneal confocal microscopy (IVCCM) along with their refractive outcomes were collected at 1 week, 1 month, 3 months and 6 months postoperatively. One-way analysis of variance (ANOVA) was used to compare the parameters among the three groups.

The SNPs in the three groups all decreased after surgery and revealed a gradual increasing trend during the 6-month follow-up. The values of the quantitative nerve metrics were significantly lower in the 110 μm group than in the 120 μm and 130 μm groups, especially at 1 week postoperatively. No difference was detected between the 120 μm and 130 μm groups at any time point. Both Langerhans cells and keratocytes were activated after surgery, and the activation was alleviated during the follow-up.

The SMILE surgeries with 110 μm, 120 μm or 130 μm cap thickness design achieved good efficacy, safety, accuracy and stability for moderate to high myopic correction while the thicker corneal cap was more beneficial for corneal nerve regeneration.

To analyze the changing trend of CH and CRF values under different influencing factors in T2DM patients. A total of 650 patients with T2DM were included. We discovered that the course of T2DM, smoking history, BMI, and FBG, DR, HbA1c, TC, TG, and LDL-C levels were common risk factors for T2DM, while HDL-C levels were a protective factor. Analyzing the CH and CRF values according to the course of diabetes, we discovered that as T2DM continued to persist, the values of CH and CRF gradually decreased. Moreover, with the increase in FBG levels and the accumulation of HbA1c, the values of CH and CRF gradually decreased. In addition, in patients with HbA1c (%) > 12, the values of CH and CRF decreased the most, falling by 1.85 ± 0.33 mmHg and 1.28 ± 0.69 mmHg, respectively. Compared with the non-DR group, the CH and CRF values gradually decreased in the mild-NPDR, moderate-NPDR, severe-NPDR and PDR groups, with the lowest CH and CRF values in the PDR group. In patients with T2DM, early measurement of corneal biomechanical properties to evaluate the change trend of CH and CRF values in different situations will help to identify and prevent diabetic keratopathy in a timely manner.

The aim of this study was to investigate age-related changes in corneal nerves and corneal epithelial cell parameters and to establish age-adjusted reference values.

A total of 7025 corneal nerve images and 4215 corneal epithelial images obtained using in vivo confocal microscopy from 281 eyes of 143 healthy participants were included. Seven corneal nerve parameters and 3 corneal epithelial cell parameters were quantified using 2 automatic analytic software and analyzed across 6 age groups ranging from 21 to 80 years.

There was a declining trend in all 7 nerve parameters with advancing age. In particular, corneal nerve fiber length and corneal nerve fiber density demonstrated a significant decrease in subjects aged 65 years or older compared with subjects younger than 65 years (10.8 ± 2.6 mm/mm 2 vs. 9.9 ± 2.0 mm/mm 2 , P = 0.011 in corneal nerve fiber length; 15.8 ± 5.2 fibers/mm 2 vs. 14.4 ± 4.3 fibers/mm 2 , P = 0.046 in corneal nerve fiber density), whereas corneal nerve fractal dimension demonstrated a borderline significant decrease ( P = 0.057). Similarly, there was a general declining trend in all epithelial cell parameters with advancing age. Corneal epithelial cell circularity was significantly lower in subjects aged 65 years and older as compared to subjects younger than 65 years (0.722 ± 0.021 μm 2 vs. 0.714 ± 0.021 μm 2 ; P = 0.011).

Advancing age results in reduced corneal nerve metrics and alteration of corneal cell morphology. Aging effects should be considered when evaluating patients with corneal neuropathy.

Some of the earliest studies of glycans were performed on mammalian corneas and lenses with many of the key concepts we currently recognize as being fundamental to our understanding of basic cell biology arising from these studies. Proteoglycans and their GAG side chains are essential components of the ECM of the lens capsule. They also are present in the anterior corneal epithelial basement membrane and the posterior (Decemet's) basement membrane, and they organize collagen fiber diameters and spacing in the corneal stroma to maintain stromal clarity. Studies using genetically engineered mice and characterization of spontaneously arising mutations in genes controlling proteoglycan synthesis have generated new insight into the roles played by proteoglycans in signal transduction. We now know that proteoglycans and GAGs can regulate cell signaling and the maintenance of avascularity and immune privilege that are hallmarks of these tissues. In addition, proteoglycan-rich matrices provide the pathways for immune cells to populate the surface of the lens as a response to corneal wounding and in a model of Experimental Autoimmune Uveitis. Here we describe what is known about proteoglycans and GAGs in the cornea and lens. This knowledge has begun to provide promising leads into new proteoglycan-based treatments aimed at restoring and maintaining homeostasis in the cornea. Future studies are needed to determine how these new drugs impact the recruitment of immune cells to the lens for functions in restoring/maintaining homeostasis in the eye.

To characterize the regional variations in corneal epithelial cell density and morphology using in vivo confocal microscopy (IVCM).

Corneal imaging (IVCM) at 10 locations was performed; corneal apex (i.e., the center), immediately anterior to the corneal nerve whorl (i.e., slightly inferior to the apex), and four quadrants (superior, nasal, inferior, and temporal) both at 1.5 mm and 4.5 mm from the corneal apex (corresponding to 3 mm central and 9 mm peripheral diameter rings). The data of 21 young adults, aged 18 to 35 years, were analyzed. Cell morphometric parameters, including cell density, area, perimeter, Feret diameter, and circularity, were measured for basal and wing cells using Image J software.

There was a significant difference in basal cell density (BCD) ( P <0.001) and wing cell density (WCD) ( P <0.001) for different corneal locations. The BCD (mean±SD: 8,839±416 cells/mm 2 ) and WCD (mean±SD: 5,932±310 cells/mm 2 ) were highest at the corneal nerve whorl compared with all other corneal locations. There were significant differences in wing cell area ( P <0.001), perimeter ( P <0.001), Feret diameter ( P <0.001), and circularity ( P <0.001) at varying corneal locations.

There are significant regional variations in corneal epithelial cell density and morphology. The BCD and WCD was highest anterior to the corneal nerve whorl.

To study potential corneal reinnervation and recovery of corneal sensation in patients with severe neurotrophic keratopathy (NK) secondary to herpes zoster ophthalmicus (HZO) after treatment with topical autologous serum tears (AST).

Four cases of HZO with severe NK were followed clinically and by serial laser in vivo confocal microscopy (IVCM, HRT3/RCM, Heidelberg Engineering) before and during treatment with 20% AST drops eight times a day. Two masked observers reviewed the IVCM images and assessed corneal nerve alterations.

At baseline, all patients had complete loss of corneal sensation. In addition, IVCM showed complete lack of the subbasal corneal nerve plexus in all patients. All four patients were refractory to conventional therapies and were treated with AST drops. All patients demonstrated significant nerve regeneration by IVCM within 3-7 months of treatment. The total nerve density increased to a mean ± SEM of 10,085.88±2,542.74 μm/mm2 at the last follow up. Corneal sensation measured by Cochet-Bonnet esthesiometry improved to a mean ± SEM of 3.50±1.30 cm. Interestingly, 3 of 4 patients developed stromal keratitis with ulceration within weeks of corneal reinnervation, which was reversed by adding topical steroids.

Autologous serum tears are effective in restoring corneal subbasal nerves and sensation in patients with severe NK secondary to HZO. However, this group of patients may require concurrent topical immunomodulation and antiviral therapy while on AST to prevent stromal keratitis.

Umbilical cord blood-derived therapeutics, such as serum (UCS) and platelet-rich plasma (UCPRP), are popular treatment options in clinical trials and can potentially be utilized to address a clinically unmet need caused by preservatives, specifically benzalkonium chloride (BAK), present in ophthalmic formulations. As current clinical interventions for secondary injuries caused by BAK are suboptimal, this study will explore the feasibility of utilizing UCS and UCPRP for cornea treatment and investigate the underlying mechanisms associated with this approach.

Mice's corneas were administered BAK to induce damage. UCS and UCPRP were then utilized to attempt to treat the injuries. Ocular tests were performed on the animals to evaluate recovery, while immunostaining, RNA-seq, and subsequent bioinformatics analysis were conducted to investigate the treatment mechanism.

BAK administration led to widespread inflammatory responses in the cornea. Subsequent treatment with UCS and UCPRP led to the downregulation of immune-related 'interactions between cytokine receptors' and 'IL-17 signaling' pathways. Although axonal enhancers such as Ngf, Rac2, Robo2, Srgap1, and Rock2 were found to be present in the injured group, robust axonal regeneration was observed only in the UCS and UCPRP treatment groups. Further analysis revealed that, as compared to normal corneas, inflammation was not restored to pre-injury levels post-treatment. Importantly, Neuropeptide Y (Npy) was also involved in regulating immune responses, indicating neuroimmune axis interactions.

Cord blood-derived therapeutics are feasible options for overcoming the sustained injuries induced by BAK in the cornea. They also have potential applications in areas where axonal regeneration is required.