Ocular surface complications in children undergoing general anaesthesia: A prospective observational study.

OBJECTIVE: Ophthalmic complications frequently occur after procedures requiring general anaesthesia, but their incidence is widely variable and not well reported in the paediatric population. The aim was to identify the incidence and possible risk factors of postoperative ocular surface complications in a tertiary care centre. METHODS AND ANALYSIS: This is a prospective study for paediatric patients undergoing general anaesthesia. An ophthalmologist performed the ocular examination after surgery. Parameters assessed were tear breakup time, punctate epithelial erosions and corneal abrasions. Multivariate logistic regression model was used to assess risk factors. RESULTS: A total of 108 paediatric patients were recruited, 36.1% showed abnormal corneal finding: 32 (29.6%) had decreased tear breakup time, three (2.7%) had punctate epithelial erosions, three (2.7%) had both punctate epithelial erosions and decreased tear breakup time and one (0.9%) was found to have a unilateral corneal abrasion postoperatively. A higher rate of corneal complications was noted with younger age, prolonged surgery and surgery in the head and neck region. CONCLUSION: The rate of postoperative corneal abnormalities in children undergoing general anaesthesia was 36.1%, associated with younger age, prolonged surgery and surgery in the head and neck region.

Erratum: Single cell analysis of short-term dry eye induced changes in cornea immune cell populations.

[This corrects the article DOI: 10.3389/fmed.2024.1362336.].

Molecular detection of lacrimal apparatus and ocular surface - related ABC transporter genes.

The ocular system is in constant interaction with the environment and with numerous pathogens. The ATP-binding cassette (ABC) transporters represent one of the largest groups among the transmembrane proteins. Their relevance has been demonstrated for their defense function against biotic and abiotic stress factors, for metabolic processes in tumors and for their importance in the development of resistance to drugs. The aim of this study was to analyze which ABC transporters are expressed at the ocular surface and in the human lacrimal apparatus. Using RT-PCR, all ABC transporters known to date in humans were examined in tissue samples from human cornea, conjunctiva, meibomian glands and lacrimal glands. The RT-PCR analyses revealed the presence of all ABC transporters in the samples examined, although the results for some of the 48 transporters known in human and analyzed were different in the various tissues. The present results provide information on the expression of ABC transporters at the mRNA level on the ocular surface and in the lacrimal system. Their detection forms the basis for follow-up studies at the protein level, which will provide more information about their physiological significance at the ocular surface and in the lacrimal system and which may explain pathological effects such as drug resistance.

Approach to Immune-mediated Ocular Diseases.

Immune-mediated ocular inflammation is a common clinical diagnosis reached for horses with keratitis and uveitis. This diagnosis is made as a diagnosis of exclusion following a thorough effort to rule out an underlying cause for the inflammation, most importantly infectious and neoplastic disease. Practically, response to ophthalmic and systemic anti-inflammatory or immunomodulatory medications is used to support a diagnosis of immune-mediated ocular inflammation; however, such medications are often contraindicated in the face of infection or neoplasia. This article will summarize our current understanding and approach to the diagnosis and management of immune-mediated keratitis and recurrent or insidious uveitis in horses.

Cell therapy in the cornea: the emerging role of microenvironment.

The cornea is an ideal testing field for cell therapies. Its highly ordered structure, where specific cell populations are sequestered in different layers, together with its accessibility, has allowed the development of the first stem cell-based therapy approved by the European Medicine Agency. Today, different techniques have been proposed for autologous and allogeneic limbal and non-limbal cell transplantation. Cell replacement has also been attempted in cases of endothelial cell decompensation as it occurs in Fuchs dystrophy: injection of cultivated allogeneic endothelial cells is now in advanced phases of clinical development. Recently, stromal substitutes have been developed with excellent integration capability and transparency. Finally, cell-derived products, such as exosomes obtained from different sources, have been investigated for the treatment of severe corneal diseases with encouraging results. Optimization of the success rate of cell therapies obviously requires high-quality cultured cells/products, but the role of the surrounding microenvironment is equally important to allow engraftment of transplanted cells, to preserve their functions and, ultimately, lead to restoration of tissue integrity and transparency of the cornea.

Outcomes after reversed corneal graft rejection: a report from the European VISICORT project.

OBJECTIVE: This study aims to describe the outcome of corneal grafts, both low risk and high risk, after successfully reversed immunological rejection. METHODS: Datasets on reversed rejection episodes in penetrating and endothelial keratoplasties between 2014 and 2019 (n=876) were extracted from the Adverse Immune Signatures and their Prevention in Corneal Transplantation database, which contains the prospectively and consecutively collected corneal transplants from five European centres. Stratified by the preoperatively determined risk status for immunological rejection, the outcome parameters analysed included visual acuity, intraocular pressure, endothelial cell density and central corneal thickness before and after reversed rejection episodes. RESULTS: Fourty-seven (52%) out of a total of 91 identified rejection episodes were successfully reversed and were available for analysis (23 penetrating and 24 endothelial keratoplasties). No statistically significant change was found for any of the parameters studied between the values before and the values 3 months after the rejection episode, irrespective of the preoperative risk status. CONCLUSION: The outcome of corneal grafts that survive immunological rejection may be clinically indistinguishable from the state before immunological rejection, irrespective of graft type and risk status. These findings support clinicians by providing information on prognosis after reversed rejection episodes and by giving patients realistic expectations regarding the outcome.

[A randomized study of subconjonctival bevacizumab (Avastin®) injection for corneal neovascularization]. / Étude randomisée de l'injection sous-conjonctivale de bévacizumab (Avastin®) dans la néo-vascularisation cornéenne.

PURPOSE: The goal of this phase III, comparative, multicentric, randomized, double-blinded clinical trial was to investigate the superiority of subconjunctival bevacizumab injections versus placebo in the treatment of corneal neovascularization. PATIENTS AND METHODS: We included 38 eyes (38 patients) with corneal neovascularization. Twenty patients received bevacizumab and 18 placebos. Patients received 3 monthly injections of either 5mg (0.2mL) bevacizumab or placebo. The main criteria of success was reduction of the surface area of corneal neovascularization after 3months (M3) versus baseline, as measured using semi-automatic analysis of color photographs. RESULTS: The percentage of neovascularized corneal surface decreased by -8.6%±32.8 with bevacizumab, versus -2.6%±20.8 with placebo (p=0.5284). Four patients were determined to be responders (reduction of more than 30%), 3 in the bevacizumab group and 1 in the placebo group, all with neovascularization of less than 1year duration. When restricting the analysis to neovascularization of less than 1 year duration, the difference approached the threshold for significance (-31.8%±42.4 in the bevacizumab group and -0.9%±23.1 in the placebo group) (p=0.0637), as well as the number of responders (3/6 in the bevacizumab group versus 1/10 in the placebo group) (p=0.1181). No serious adverse event was reported. CONCLUSION: This study shows the efficacy of subconjunctival bevacizumab injection in the reduction of neovascularized corneal surface area versus placebo, but only when the neovascularization has been present less than 1year. Nevertheless, the study did not attain the statistical power to pass the threshold of significance.

Automated Measurement and Three-Dimensional Fitting of Corneal Ulcerations and Erosions via AI-Based Image Analysis.

PURPOSE: Artificial intelligence (AI)-tools hold great potential to compensate for missing resources in health-care systems but often fail to be implemented in clinical routine. Intriguingly, no-code and low-code technologies allow clinicians to develop Artificial intelligence (AI)-tools without requiring in-depth programming knowledge. Clinician-driven projects allow to adequately identify and address real clinical needs and, therefore, hold superior potential for clinical implementation. In this light, this study aimed for the clinician-driven development of a tool capable of measuring corneal lesions relative to total corneal surface area and eliminating inaccuracies in two-dimensional measurements by three-dimensional fitting of the corneal surface. METHODS: Standard slit-lamp photographs using a blue-light filter after fluorescein instillation taken during clinical routine were used to train a fully convolutional network to automatically detect the corneal white-to-white distance, the total fluorescent area and the total erosive area. Based on these values, the algorithm calculates the affected area relative to total corneal surface area and fits the area on a three-dimensional representation of the corneal surface. RESULTS: The developed algorithm reached dice scores >0.9 for an automated measurement of the relative lesion size. Furthermore, only 25% of conventional manual measurements were within a ± 10% range of the ground truth. CONCLUSIONS: The developed algorithm is capable of reliably providing exact values for corneal lesion sizes. Additionally, three-dimensional modeling of the corneal surface is essential for an accurate measurement of lesion sizes. Besides telemedicine applications, this approach harbors great potential for clinical trials where exact quantitative and observer-independent measurements are essential.

Incidence and Mitigation of Corneal Pseudomicrocysts Induced by Antibody-Drug Conjugates (ADCs).

Purpose of Review: This study is to highlight the incidence of corneal pseudomicrocysts in FDA-approved antibody-drug conjugates (ADCs), and success of preventive therapies for pseudomicrocysts and related ocular surface adverse events (AEs). Recent Findings: ADCs are an emerging class of selective cancer therapies that consist of a potent cytotoxin connected to a monoclonal antibody (mAb) that targets antigens expressed on malignant cells. Currently, there are 11 FDA-approved ADCs with over 164 in clinical trials. Various AEs have been attributed to ADCs, including ocular surface AEs (keratitis/keratopathy, dry eye, conjunctivitis, blurred vision, corneal pseudomicrocysts). While the severity and prevalence of ADC-induced ocular surface AEs are well reported, the reporting of corneal pseudomicrocysts is limited, complicating the development of therapies to prevent or treat ADC-related ocular surface toxicity. Summary: Three of 11 FDA-approved ADCs have been implicated with corneal pseudomicrocysts, with incidence ranging from 41 to 100% of patients. Of the six ADCs that reported ocular surface AEs, only three had ocular substudies to investigate the benefit of preventive therapies including topical steroids, vasoconstrictors, and preservative-free lubricants. Current preventive therapies demonstrate limited efficacy at mitigating pseudomicrocysts and other ocular surface AEs.

The Impact of Vaping on the Ocular Surface: A Systematic Review of the Literature.

Background: The use of electronic cigarettes has become increasingly popular in recent years. However, the impact that electronic cigarettes have on the ocular surface is not well known. Therefore, the aim of this review is to explore the current literature on the acute and chronic sequelae of electronic cigarettes on the ocular surface. Methods: A systematic review of the literature was undertaken by keyword searching on the Embase, Medline, and Web of Science databases. Articles identified through the search underwent title/abstract screening, full-text screening, and data extraction. Results: A total of 18 studies were included in this review. Non-intended ocular surface exposures and intended exposures on the ocular surface were found to be associated with the use of electronic cigarettes. Conclusions: The impact of vaping on the ocular surface is not benign. There are significant risks that vaping can pose to the ocular surface. Hence, it is necessary to develop appropriate risk communication tools given the increasing popularity of this activity. Additionally, future long-term studies are needed to better understand the long-term impacts of vaping on the ocular surface given the lack of current data.

Evaluating keratometry and corneal astigmatism data from biometers and anterior segment tomographers and mapping to reconstructed corneal astigmatism.

BACKGROUND: To compare results from different corneal astigmatism measurement instruments; to reconstruct corneal astigmatism from the postimplantation spectacle refraction and toric intraocular lens (IOL) power; and to derive models for mapping measured corneal astigmatism to reconstructed corneal astigmatism. METHODS: Retrospective single centre study involving 150 eyes treated with a toric IOL (Alcon SN6AT, DFT or TFNT). Measurements included IOLMaster 700 keratometry (IOLMK) and total keratometry (IOLMTK), Pentacam keratometry (PK) and total corneal refractive power in 3 and 4 mm zones (PTCRP3 and PTCRP4), and Aladdin keratometry (AK). Regression-based models mapping the measured C0 and C45 components (Alpin's method) to reconstructed corneal astigmatism were derived. RESULTS: Mean C0 components were 0.50/0.59/0.51 dioptres (D) for IOLMK/PK/AK; 0.2/0.26/0.31 D for IOLMTK/PTCRP3/PTCRP4; and 0.26 D for reconstructed corneal astigmatism. All corresponding C45 components ranged around 0. The prediction models had main diagonal elements lower than 1 with some crosstalk between C0 and C45 (nonzero off-diagonal elements). Root-mean-squared residuals were 0.44/0.45/0.48/0.51/0.50/0.47 D for IOLMK/IOLMTK/PK/PTCRP3/PTCRP4/AK. CONCLUSIONS: Results from the different modalities are not consistent. On average IOLMTK/PTCRP3/PTCRP4 match reconstructed corneal astigmatism, whereas IOLMK/PK/AK show systematic C0 offsets of around 0.25 D. IOLMTK/PTCRP3/PTCRP4. Prediction models can reduce but not fully eliminate residual astigmatism after toric IOL implantation.

Increased tolerance to commonly used antibiotics in a Pseudomonas aeruginosa ex vivo porcine keratitis model.

Introduction. Bacterial keratitis, particularly caused by Pseudomonas aeruginosa, is challenging to treat because of multi-drug tolerance, often associated with the formation of biofilms. Antibiotics in development are typically evaluated against planktonic bacteria in a culture medium, which may not accurately represent the complexity of infections in vivo.Hypothesis/Gap Statement. Developing a reliable, economic ex vivo keratitis model that replicates some complexity of tissue infections could facilitate a deeper understanding of antibiotic efficacy, thus aiding in the optimization of treatment strategies for bacterial keratitis.Methodology. Here we investigated the efficacy of three commonly used antibiotics (gentamicin, ciprofloxacin and meropenem) against Pseudomonas aeruginosa cytotoxic strain PA14 and invasive strain PA01 using an ex vivo porcine keratitis model.Results. Both strains of P. aeruginosa were susceptible to the MIC of the three tested antibiotics. However, significantly higher concentrations were necessary to inhibit bacterial growth in the minimum biofilm eradication concentration (MBEC) assay, with both strains tolerating concentrations greater than 512 mg l-1 of meropenem. When MIC and higher concentrations than MBEC (1024 mg l-1) of antibiotics were applied, ciprofloxacin exhibited the highest potency against both P. aeruginosa strains, followed by meropenem, while gentamicin showed the least potency. Despite this, none of the antibiotic concentrations used effectively cleared the infection, even after 18 h of continuous exposure.Conclusions. Further exploration of antibiotic concentrations and aligning dosing with clinical studies to validate the model is needed. Nonetheless, our ex vivo porcine keratitis model could be a valuable tool for assessing antibiotic efficacy.

The Potential Reversible Transition between Stem Cells and Transient-Amplifying Cells: The Limbal Epithelial Stem Cell Perspective.

Stem cells (SCs) undergo asymmetric division, producing transit-amplifying cells (TACs) with increased proliferative potential that move into tissues and ultimately differentiate into a specialized cell type. Thus, TACs represent an intermediary state between stem cells and differentiated cells. In the cornea, a population of stem cells resides in the limbal region, named the limbal epithelial stem cells (LESCs). As LESCs proliferate, they generate TACs that move centripetally into the cornea and differentiate into corneal epithelial cells. Upon limbal injury, research suggests a population of progenitor-like cells that exists within the cornea can move centrifugally into the limbus, where they dedifferentiate into LESCs. Herein, we summarize recent advances made in understanding the mechanism that governs the differentiation of LESCs into TACs, and thereafter, into corneal epithelial cells. We also outline the evidence in support of the existence of progenitor-like cells in the cornea and whether TACs could represent a population of cells with progenitor-like capabilities within the cornea. Furthermore, to gain further insights into the dynamics of TACs in the cornea, we outline the most recent findings in other organ systems that support the hypothesis that TACs can dedifferentiate into SCs.

Intravital imaging of the human cornea reveals the differential effects of season on innate and adaptive immune cell morphodynamics.

PURPOSE: While the external environment has been shown to shape the systemic human immune landscape, defining the in vivo immune status of peripheral tissues has remained a technical challenge. We recently developed functional in vivo confocal microscopy (Fun-IVCM) for dynamic, longitudinal imaging of corneal immune cells in living humans. This study investigated the effect of seasonal-driven environmental factors on the density, morphology and dynamic behavior of human corneal immune cell subsets. DESIGN: Longitudinal, observational clinical study. PARTICIPANTS: Sixteen healthy participants (18-40 years) attended two visits in distinct seasons in Melbourne, Australia (Visit 1: Spring/Summer: November-December 2021; Visit 2: Autumn/Winter: April-June 2022). METHODS: Environmental data were collected over each period. Participants underwent ocular surface examinations and corneal Fun-IVCM (Heidelberg HRT-3, Rostock Corneal Module). Volume scans (80µm) were acquired at 5.5±1.5 minute intervals, for up to five timepoints. Time-lapse videos were created to analyze corneal immune cells, comprising epithelial T cells and dendritic cells (DCs), and stromal macrophages. Tear cytokines were analyzed using multiplex bead-based immunoassay. MAIN OUTCOME MEASURES: Difference in the density, morphological and dynamic parameters of corneal immune cell subsets over the study periods. RESULTS: Visit 1 was characterized by higher temperature, lower humidity, and higher air particulate and pollen levels than Visit 2. Clinical ocular surface parameters, and the density of immune cell subsets were similar across visits. At Visit 1 (Spring/Summer), corneal epithelial DCs were larger and more elongated, with a lower dendrite probing speed (0.38±0.21 vs 0.68±0.33µm/min, p<0.001) relative to Visit 2; stromal macrophages were more circular and had less dynamic activity (Visit 1: 7.2±1.9 vs Visit 2: 10.3±3.7 'dancing index', p<0.001). T cell morphology and dynamics were unchanged across periods. Basal tear levels of IL-2 and CXCL10 were lower during Spring/Summer. CONCLUSION: This novel study shows that the in vivo morphodynamics of innate corneal immune cells (DCs, macrophages) are modified by environmental factors, but such effects are not evident for adaptive immune cells (T cells). The cornea is a potential non-invasive, in vivo 'window' to season-dependent changes to the human immune system, with capacity to yield new insight into environmental influences on immune regulation.

Elevated Neutrophils and reduced NK cells are associated with altered tear molecular signatures and clinical sequelae of chronic ocular Stevens-Johnson Syndrome.

PURPOSE: Stevens-Johnson syndrome (SJS) is characterised as an immuno-inflammatory condition with potentially blinding ocular sequelae. Therefore, we have investigated the ocular surface immune cell profile and correlated it with secreted tear molecular factors and clinical ocular sequelae in SJS patients. METHODS: 21 patients (42 eyes) with chronic ocular SJS and 16 healthy controls (20 eyes) were included in the study. Severity, types of keratopathies and ocular surface(OS) manifestations were determined. OS wash samples from study subjects were used to determine the status of 13 immune cell subsets using flow cytometry. Levels of 42 secreted immuno-inflammatory factors were measured by flow cytometry-based multiplex ELISA in tear samples. RESULTS: Neutrophils (Total, activated), neutrophils/NK cells ratio, neutrophils/T cells ratio were significantly (p<0.05) elevated in SJS, while, proportions of T cells and NKT cells were significantly lower in SJS patients. Positive association between neutrophils and chronic ocular surface complication score (COCS) was observed, whereas, a negative association was noted between NK cells and COCS. Tear fluid levels of IL-6, IL-8, IL-18, IFNα/ß/γ, TNFα, LIF, IL-8, HGF, sTNFR-I, NGAL, Granzyme, Perforins, MMP9/TIMP1 ratio were significantly higher in SJS. Loss of Limbal niche correlated significantly with immune profile and clinical sequelae. Increased neutrophils, decreased NK cells and specific set of altered secreted immuno-inflammatory mediators including bFGF, and IL-8 were observed in SJS patients with different types of keratopathies compared to those without keratopathy. CONCLUSION: Distinct ocular surface immune profile variations were observed to correlate with clinical stages of chronic ocular SJS. Our findings uncover novel mechanisms and potential for targeted therapy in chronic ocular SJS patients.

The Spiral of Tillaux: dead on accurate; a cadaveric study.

INTRODUCTION: The Spiral of Tillaux describes the historically accepted insertion distances of the medial rectus, inferior rectus, lateral rectus, and superior rectus from the limbus: 5.5 mm, 6.5 mm, 6.9 mm, and 7.7 mm, respectively. The corneal diameters are historically accepted to be 11.7 mm horizontally and 10.6 mm vertically in adults. We investigated the variability of the insertion distances of the extraocular rectus muscles from the limbus as well as the corneal diameters using eyes from human cadavers and compared our measurements to these historically accepted measurements. METHODS: A sample of 60 eyes were included. For each eye, a 360 peritomy was conducted and the conjunctiva bluntly dissected to view the sclera. Muscle hooks were utilized to isolate the extraocular rectus muscles. Calipers were used to measure the insertion distances of the rectus muscles as well as the corneal diameters. RESULTS: The mean rectus muscle insertions distances from the limbus were medial 5.28 mm, inferior 5.72 mm, lateral 6.40 mm, and superior 6.78 mm. These insertion distances were shorter than the historical benchmarks (p < .01). However, observed maximum distances of the rectus muscles were all greater than the historically accepted benchmarks, with the medial, inferior, lateral, and superior rectus muscles being 6.4 mm, 7.3 mm, 7.4 mm, and 7.8 m from the limbus, respectively. The mean width and height of the cornea were 11.7 mm and 10.7 mm, respectively, and similar to the expected ranges. CONCLUSION: This study concludes that variability does exist from the historically accepted Spiral of Tillaux measurements. In addition, significant variation exists between male and female rectus muscle insertions. However, we did confirm that the rectus muscles followed the same spiral pattern described by the Spiral of Tillaux and concluded that the corneal diameters are consistent with previously accepted values.

Investigation of mechanical strength and structure of corneal graft-host junction.

Dehiscence is a common complication of corneal transplant surgery involving separating the graft from the host eye. The present article aims to investigate fundamental insights into the mechanical and structural aspects of the graft-host junction (GHJ) of a graft that survived in a patient for 13 years after penetrating keratoplasty (PK). Additionally, it adopts the sutur retention strength (SRS) test procedure defined in ISO:7198-2016 and aims to provide a comprehensive test protocol to study the biomechanics of the GHJ in extracted PK buttons. A 9 mm corneal button with GHJ was extracted from a 46-year-old patient who underwent PK 13 years back. The strength of the GHJ was quantified using the SRS test. Corresponding control results were obtained from the SRS tests of a corneoscleral button with no history of any refractive procedure. Birefringence, histological, and scanning electron microscopy (SEM) imaging were used to visualize the microstructural details of the GHJ. The strength of the GHJ was observed to be ten times lower than the native cornea. Histopathological features, such as fragmented Bowman's layer, and fibrosis with a clear demarcation line between host and graft tissue, were observed at the GHJ, suggesting a weak bond across the GHJ. The low strength of the GHJ in PK indicates the high susceptibility of the GHJ towards wound dehiscence.

Efficacy of 3% diquafosol long-acting eye drops in dry eye patients treated for three months.

PURPOSE: To investigate changes in the ocular surface and subjective symptoms during a three months administration of 3% diquafosol long-acting (DQL) eye drops. STUDY DESIGN: Prospective observational study. METHODS: DQL eye drops were administered as the sole treatment for all patients, including those in the group where DQL eye drops were newly prescribed (New DQL) and the group who switched from 3% diquafosol (DQS) eye drops (Switched DQL) in this prospective study. Each group underwent assessment of tear meniscus height (TMH), ocular surface disease index (OSDI), fluorescein break-up time (FBUT), fluorescein score, and Schirmer 1 test before DQL administration, at one month, and at three months. Changes in ocular surface scores and subjective symptoms at each time point were analyzed. RESULTS: The study included a total of 63 eyes of 63 patients, with a mean age of 60.3 ±14.6 (SD). Among them, 29 patients (20 women) were in the New DQL group, and 34 patients (24 women) were in the Switched DQL group. Both the New DQL and Switched DQL groups showed significant improvements in TMH, OSDI, FBUT, Fluorescein Score, and Schirmer 1 test after three months of DQL eye drop administration. CONCLUSION: DQL eye drops have the potential to improve ocular scores and subjective symptoms in patients with DE over a three months period, regardless of whether it is newly initiated or as a switch from DQS eye drops.

Biologicals and Biomaterials for Corneal Regeneration and Vision Restoration in Limbal Stem Cell Deficiency.

The mammalian cornea is decorated with stem cells bestowed with the life-long task of renewing the epithelium, provided they remain healthy, functional, and in sufficient numbers. If not, a debilitating disease known as limbal stem cell deficiency (LSCD) can develop causing blindness. Decades after the first stem cell (SC) therapy is devised to treat this condition, patients continue to suffer unacceptable failures. During this time, improvements to therapeutics have included identifying better markers to isolate robust SC populations and nurturing them on crudely modified biological or biomaterial scaffolds including human amniotic membrane, fibrin, and contact lenses, prior to their delivery. Researchers are now gathering information about the biomolecular and biomechanical properties of the corneal SC niche to decipher what biological and/or synthetic materials can be incorporated into these carriers. Advances in biomedical engineering including electrospinning and 3D bioprinting with surface functionalization and micropatterning, and self-assembly models, have generated a wealth of biocompatible, biodegradable, integrating scaffolds to choose from, some of which are being tested for their SC delivery capacity in the hope of improving clinical outcomes for patients with LSCD.