Keratoconus International Consortium (KIC)- advancing keratoconus research.

CLINICAL RELEVANCE: The Keratoconus International Consortium (KIC) will allow better understanding of keratoconus. BACKGROUND: Keratoconus is a disorder characterised by corneal elevation and thinning, leading to reduced vision. The current gaps in understanding of this disease will be discussed and the need for a multi-pronged and multi-centre engagement to enhance our understanding of keratoconus will be highlighted. DESIGN: KIC has been established to address the gaps in our understanding of keratoconus with the aim of collecting baseline as well as longitudinal data on several fields. PARTICIPANTS: Keratoconus and control (no corneal condition) subjects from different sites globally will be recruited in the study. METHODS: KIC collects data using an online, secure database, which enables standardised data collection at member sites. Data fields collected include medical history, clinical features, quality of life and economic burden questionnaires and possible genetic sample collection from patients of different ethnicities across different geographical locations. RESULTS: There are currently 40 Australian and international clinics or hospital departments who have joined the KIC. Baseline data has so far been collected on 1130 keratoconus patients and indicates a median age of 29.70 years with 61% being male. A total of 15.3% report a positive family history of keratoconus and 57.7% self-report a history of frequent eye rubbing. CONCLUSION: The strength of this consortium is its international, collaborative design and use of a common data collection tool. Inclusion and analyses of cross-sectional and longitudinal data will help answer many questions that remain in keratoconus, including factors affecting progression and treatment outcomes.

Electro-compacted collagen for corneal epithelial tissue engineering.

Bioengineered corneal substitutes offer a solution to the shortage of donor corneal tissue worldwide. As one of the major structural components of the cornea, collagen has shown great potential for tissue-engineered cornea substitutes. Herein, free-standing collagen membranes fabricated using electro-compaction were assessed in corneal bioengineering application by comparing them with nonelectro-compacted collagen (NECC). The well-organized and biomimetic fibril structure resulted in a significant improvement in mechanical properties. A 10-fold increase in tensile and compressive modulus was recorded when compared with NECC membranes. In addition to comparable transparency in the visible light range, the glucose permeability of the electro-compacted collagen (ECC) membrane is higher than that of the native human cornea. Human corneal epithelial cells adhere and proliferate well on the ECC membrane, with a large cell contact area observed. The as-described ECC has appropriate structural, topographic, mechanical, optical, glucose permeable, and cell support properties to provide a platform for a bioengineered cornea; including the outer corneal epithelium and potentially deeper corneal tissues.

Visual and Refractive Efficacy of Panoptix Toric Intraocular Lens in a Clinical Setting.

Purpose: Trifocal Intraocular Lenses (IOLs) were developed to provide patients with effective near, intermediate and distance vision, thus minimizing spectacle dependency. Residual astigmatism has previously been shown to impact unaided visual acuity across all distances; therefore, to optimise the expected outcomes, consideration of preoperative corneal astigmatism is essential. The purpose of this study was to provide a real-world, multi-site review of visual and refractive outcomes in eyes undergoing implantation with the Panoptix Trifocal toric IOL platform. Patients and Methods: This study represents a two-fold approach. Patients who had previously undergone routine cataract removal and IOL insertion with the Panoptix Toric IOL were retrospectively analysed for routine efficacy and safety endpoints ("Retrospective Cohort"). Data was retrieved from the preoperative, surgical and postoperative visits (range 2-6 weeks). A further subset of patients undergoing lens removal and bilateral Panoptix Toric IOL insertion were identified at surgery ("Qualitative Cohort"). These patients underwent additional testing inclusive of quality of vision questionnaire and bilateral defocus curve. Results: A total of 466 eyes of 254 patients were included in the retrospective cohort. Between 91% and 98% of eyes, respectively, were within 0.50D and 1.00D of target. Mean absolute difference from Spherical Equivalent (SE) target was 0.22 ± 0.24Ds. Following surgery, 94% of eyes demonstrated a refractive astigmatism of 0.50D or less. Further, 61% eyes achieved uncorrected distance visual acuity (UDVA) of 20/20 or better, increasing to 94% achieving 20/32 or better. Seventy percent of eyes unilaterally achieved N5 unaided and 66.0% achieved N8 or better at intermediate. In the qualitative cohort, no patient described any symptom as significant or requested explant. Conclusion: In a real-world setting, the PanOptix toric trifocal IOL continues to demonstrate refractive accuracy and good visual performance at all focal distances. This IOL also exhibited good quality of vision, with minimally bothersome visual disturbances or photic phenomena.

Development of an In Situ Printing System With Human Platelet Lysate-Based Bio-Adhesive to Treat Corneal Perforations.

Purpose: Corneal perforation is a clinical emergency that can result in blindness. Currently corneal perforations are treated either by cyanoacrylate glue which is toxic to corneal cells, or by using commercial fibrin glue for small perforations. Both methods use manual delivery which lead to uncontrolled application of the glues to the corneal surface. Therefore, there is a need to develop a safe and effective alternative to artificial adhesives. Methods: Previously, our group developed a transparent human platelet lysate (hPL)-based biomaterial that accelerated corneal epithelial cells healing in vitro. This biomaterial was further characterized in this study using rheometry and adhesive test, and a two-component delivery system was developed for its application. An animal trial (5 New Zealand white rabbits) to compare impact of the biomaterial and cyanoacrylate glue (control group) on a 2 mm perforation was conducted to evaluate safety and efficacy. Results: The hPL-based biomaterial showed higher adhesiveness compared to commercial fibrin glue. Treatment rabbits had lower pain scores and faster recovery, despite generating similar scar-forming structure compared to controls. No secondary corneal ulcer was generated in rabbits treated with the bio-adhesive. Conclusions: This study reports an in situ printing system capable of delivering a hPL-based, transparent bio-adhesive and successfully treating small corneal perforations. The bio-adhesive-treated rabbits recovered faster and required no additional analgesia. Translational Relevance: The developed in situ hPL bio-adhesives treatment represents a new format of treating corneal perforation that is easy to use, allows for accurate application, and can be a potentially effective and pain relief treatment.

Examining Corneal Tissue Exportation Fee and Its Impact on Equitable Allocation.

METHODS: We conducted grounded theory semistructured interviews, purposively inviting participants until themed saturation was met. Sentiment analysis was used to determine opinion. RESULTS: We interviewed n = 92 global eye tissue and eye bank professionals. We determined that corneal tissue, which is exported, costs between US $100 and US $6000 or is provided as gratis. Collectively, interviewees indicated that, globally, there were no fixed fee structures in place, and the fee was influenced by multiple factors on both export and import sides. They indicated that ultimately corneas were allocated based on the importers' ability to pay the price determined by the exporting eye bank. DISCUSSION: Allocation of corneal tissue, which is exported, is influenced by the fees charged by the exporters to meet their bottom line and the funds available to importers. Therefore, export allocation is not equitable, with those who can pay a higher fee, prioritized. Steps to guide and support exporters with the development of fee structures that promote equitable allocation are essential. This will assist both export and import eye bank development, corneal tissue access development, and those awaiting a corneal transplant.

Prevalence of tear film hyperosmolarity in 1150 patients presenting for refractive surgery assessment.

PURPOSE: To present an analysis of tear film hyperosmolarity in a large, consecutive population and evaluate the correlation of ocular and systemic conditions with tear film osmolarity (TFO). SETTING: Private practice, Sydney, Australia. DESIGN: Single-center, retrospective, consecutive cohort. METHOD: Patients undergoing screening for laser refractive surgery from October 2017 to October 2020 were retrospectively reviewed. 1404 patients (n = 1357 standard, n = 47 postrefractive) undergoing screening for laser refractive surgery from October 2017 to October 2020 were reviewed. Routine examination included TFO and Ocular Surface Disease Index (OSDI) questionnaire. TFO was conducted prior to further tests, and patients refrained from topical eyedrops minimum 2 hours before the appointment. RESULTS: 1404 patients (n = 1357 standards, n = 47 postrefractive) patients were reviewed. Mean highest TFO in the standard population was 299.12 ± 11.94 mOsm/L, with 82.3% of eyes <308 mOsm/L indicating normal tear film homeostasis. The mean intereye TFO difference was 8.17 ± 8.60 mOsm/L, with 65.2% of eyes ≤8 mOsm/L. Mean highest TFO in the postrefractive subgroup was 299.72 ± 11.00 mOsm/L, with a mean intereye difference of 9.02 ± 6.92 mOsm/L. Postrefractive surgery patients indicated higher mean OSDI values of 15.28 ± 14.46 compared with the remainder of the population 9.69 ± 10.56 (P = .012). Significant correlation was demonstrated between TFO scores and OSDI normal classification in the standard population only (P = .005, r = 0.077). The use of contact lens correlated inversely with TFO and OSDI scores (P = .000, r = -0.136, and P = .000, r = -0.152, respectively). CONCLUSIONS: To the authors' knowledge, this study represents the largest available cohort of TFO scores in a standard population presenting for refractive surgery. Although most patients were found to fall within normal ranges, a reasonable percentage were diagnosed with tear hyperosmolarity and therefore at risk for dry eye disease.

Application of Collagen I and IV in Bioengineering Transparent Ocular Tissues.

Collagens represent a major group of structural proteins expressed in different tissues and display distinct and variable properties. Whilst collagens are non-transparent in the skin, they confer transparency in the cornea and crystalline lens of the eye. There are 28 types of collagen that all share a common triple helix structure yet differ in the composition of their α-chains leading to their different properties. The different organization of collagen fibers also contributes to the variable tissue morphology. The important ability of collagen to form different tissues has led to the exploration and application of collagen as a biomaterial. Collagen type I (Col-I) and collagen type IV (Col-IV) are the two primary collagens found in corneal and lens tissues. Both collagens provide structure and transparency, essential for a clear vision. This review explores the application of these two collagen types as novel biomaterials in bioengineering unique tissue that could be used to treat a variety of ocular diseases leading to blindness.

Effects of human platelet lysate on the growth of cultured human corneal endothelial cells.

Human platelet lysate (hPL) as a replacement for foetal bovine serum (FBS) in culturing human corneal endothelium is an emerging area of interest, although there are limited studies evaluating the quality of the hPL being used. Our study aimed to evaluate variations between sources of hPL and to explore the efficacy of hPL (with and without heparin) as a replacement for FBS in culturing human corneal endothelial cells in vitro. Immortalized human corneal endothelial cells (B4G12) and primary human corneal endothelial cells (PHCEnCs, n = 11 donors, age from 36 to 85 years old) were cultured with 5% hPL or FBS. A full characterisation of the effects of hPL and FBS on cell growth was conducted using IncuCyte Zoom (percentage cell confluence and population doubling time, PDT) to analyse cell proliferation. AlamarBlue assays were used to measure cell viability. The concentration of fibrinogen, PDGF, hEGF, VEGF and bFGF in two sources of hPL were analyzed by Enzyme-linked immunosorbent assay. Expression and localization of Na+/K+-ATPase, ZO-1 and CD166 on PHCEnCs and B4G12 cells were assessed with immunofluorescence and immunoblotting. Our results showed that a significant difference in fibrinogen, hEGF and VEGF concentrations was found between two sources of hPL. Heparin impaired the positive effect of hPL on cell growth. PDT and alamarBlue showed that hPL significantly increased proliferation and viability of PHCEnCs in two of three donors, and immunostaining indicated that hPL increased ZO-1 and CD166 expression but not Na+/K+-ATPase on PHCEnCs. In addition, heterogeneities on immunopositivity of Na+/K+-ATPase and ZO-1 and morphology were found on PHCEnCs derived from an individual donor cultured with hPL medium. In conclusion, hPL showed positive effect on primary corneal endothelial cell growth, and maintenance of their cellular characteristics compared to FBS. hPL can be considered as a supplement to replace FBS in PHCEnC culture. However, the variation observed between different hPL sources suggests that a standard quality control monitoring system such as storage time and a minimal concentration of growth factors may need to be established.

Do Eye Bank Models and Competitive Practice Affect International Cornea Allocation?

PURPOSE: International export and import of corneas is dependent on the stakeholders involved in the process and how those organizations engage to move corneas from one point to another. Our article presents the pathway of corneal donation from the export nation until its use in the import nation. It presents opinion on how aspects, such as competition and promotional behaviors, the use of online systems, and third-party engagement may influence allocation. METHODS: We interviewed n = 92 international eye tissue and eye bank (EB) professionals to garner their opinion. We used saturation and sentiment methods to extract and consolidate group opinion. RESULTS: Interviewees indicated that competition and promotional behaviors existed in some EB nations-although it was not universal. They indicated that the behavioral approach used by the individual EB, rather than the act of information sharing, influenced allocation. They also indicated that organizational models and allocation systems (eg, online ordering) and engagement with nonstate actors were important in allocation practice and decision making. CONCLUSION: We mapped the pathways for corneas involved in export and import from the point of recovery to their point of transplantation. Although generalist in nature and limited by the paucity of the existing literature, our article outlines that different business models, partnerships, and applied methods influence corneal export and import.

Determining the willingness of Australians to export their corneas on death.

BACKGROUND: 12.7 million people await a corneal transplant, but 53% are without access to corneal tissue. Sharing corneal tissue across nations can provide some access, however the willingness of export populations, like Australians, to export their donation on death, has never been evaluated. Our research samples the Australian population, determining their willingness to export. MATERIALS AND METHOD: We conducted e-surveys. N = 1044 Australians participated. The sample represented the Australian population, based on population demographics. Chi-Square and bivariate correlation coefficients examined associations between categorical variables, with a sample size of N = 1044, power of 0.80, and alpha of p = 0.05. Outcome measures were based on population sampling, by exploring willingness export, through the e-survey method. RESULTS: 38% (n = 397) of respondents said yes to exportation, 23.8% (n = 248) said no, and 38.2% (n = 399) were undecided. We found no relationship between willingness to export and general demographics, though those registered on the Donatelife Register (p = < .001), and those already willing to donate their eyes (p = < .001) were significantly more willing to export. DISCUSSION: More Australians are willing to export their corneas than not, though a significant portion remain undecided. The Donatelife Register, and donation awareness, are key components of respondent decision making. Therefore, the provision of information about exportation prior to, and at the point-of-donation, is essential for assisting Australian's to decide to export or not. Further examination and development of consent-for-export systems are necessary before routine exportation is undertaken.

Supply and Demand of Domestic Corneal Tissue and Its Implications on Export Potential-Using Australia as an Example.

PURPOSE: Corneal tissue importation is only possible if another country is able to export corneas without impacting its own domestic demand. Currently, there is little evidence to indicate whether export nations have such surplus capacity and in a position to export. To explore this concept, we examined our nation, Australia, which is reported to routinely decline donations because of its ability to meet domestic corneal transplant demand. Our research offers insights and opportunities for Australia and other nations to evaluate their domestic and international supply and allocation of corneal tissue in this space. METHOD: We collated 12 months of data on collected and noncollected donations, through participating Australian Eye Banks. The explanation of why some known donors were declined or not pursued indicated if demand was met and potential surplus-for-export levels. RESULTS: There were 7.5% (n = 11,889) of deaths in Australia that were notified to Australian Eye Banks during our reporting period. Of those, 9.3% (n = 1106/11,889) were recovered and allocated, 15.7% (n = 1863/11,889) were known but declined, and 75% (n = 8920/11,889) were not pursued. Of those that were declined, 64.3% (n = 1197/1863) were declined because of limitations with service/manpower at the eye bank, whereas 35.7% (n = 666/1863) were declined because demand was met. CONCLUSIONS: Australia did not meet demand all the time, during our data period. There were adequate quantities of potential donors to support increasing recovery for domestic allocation and provide for exportation without hindrance to Australian demand. Further examination of domestic supply and demand cycles and the export process is required before routine exportation.

Should Donors Consent to Export Their Corneas? Examination of Eye Tissue and Eye Care Sector Opinion.

PURPOSE: Corneal tissue international activity is only possible because of the willingness of export populations to donate their corneas on their death. Current predonation public education campaigns and at-the-point-of-donation consent practice generally includes consent for transplantation, research, and/or training. It is unclear whether a consent-for-export step is universally included in the consent process or, indeed, whether it should. We interviewed eye tissue and eye care professionals from around the world, who exported, imported, or did neither to understand current consent-for-export awareness and determine opinion on future practice. METHOD: During wider qualitative grounded-theory semistructured interviews with sector experts, to determine whether Australia should export, we captured sector opinion on consent-for-export. We used saturation and sentiment methods to determine opinion and χ2 correlation coefficients to examine association, using an α of P = 0.05. RESULTS: We interviewed 92 individuals, 83 of whom discussed consent-for-export. Of those, 51% (42/83) demonstrated some awareness of the practice; however, there were contradictions between interviewees from the same location. Regardless of current awareness, 57% (41/72) believed donors should be informed or consented for export. Their approval did not extend to donor-directed decisions, which would allow donors to decide which nation their donation should be sent, with 62.5% (45/72) opposing that notion. CONCLUSIONS: Our research indicates that the consent-for-export practice is not universally applied by exporting nations and that eye tissue and eye care professionals have limited awareness of the practice. Universally implementing a consent-for-export step within general consent practice would improve awareness, reduce confusion, and support donor wishes.

Human Platelets and Derived Products in Treating Ocular Surface Diseases - A Systematic Review.

Human platelet products have emerged as an alternative treatment for a range of ocular surface diseases such as dry eye and corneal ulceration. With significant therapeutic potential and increasing popularity, this study aimed to conduct a systematic review to detail the various production methods involved in generating platelet-derived products, compare and analyze clinical findings across available studies, and disseminate the relative advantages, limitations, and challenges of using platelet products to treat ocular surface disease. Thirty-eight clinical studies were identified, excluding studies conducted in animals and non-English language. Studies reported clinical outcomes, which included ocular surface disease index, best-corrected visual acuity, and corneal fluorescein staining. Most clinical studies reported improved patient signs and symptoms with an increasing variety of human platelet products including platelet rich plasma eye drops, human platelet lysate and platelet gels. However, due to variations in production methods, and study designs as well as confusing terminology, it was suggested that characterization of platelet products is needed for proper evaluation across studies.

Ocular Tissue for Research in Australia: Strategies for Potential Research Utility of Surplus and Transplant-Ineligible Deceased Donations.

A 2016 Price Waterhouse Cooper Report, commissioned by the Australian Commonwealth Government's Organ and Tissue Authority, indicated that Australia had been meeting its human ocular tissue for transplant needs. It further suggested that Australia should consider exportation as a management strategy for excess tissue. Although we do not seek to discuss how the Price Waterhouse Cooper Report determined that need was being met, nor the potential value of exportation in this article, we propose that Ocular Tissue for Research (OTR), and particularly identification of donors for research, and timely access to fresh domestic tissue, be considered as an alternate or simultaneous surplus management strategy. A robust OTR system could provide long-term domestic support and investment into research and development of therapies in Australia. Such a system would also provide a meaningful donation option for those otherwise unable to donate for transplant. This article attempts to document, for the first time to our knowledge, the current recovery and distribution processes of deceased OTR in Australia. It maps the process steps, identifies the stakeholders and needs, discusses the limitations and barriers, and proposes key policy and practice reform strategies that may assist in improving access to OTR. Translational Relevance: To improve and increase access to human ocular tissue for research, and in turn, advance vision science and clinical application.

Biomimetic corneal stroma using electro-compacted collagen.

Engineering substantia propria (or stroma of cornea) that mimics the function and anatomy of natural tissue is vital for in vitro modelling and in vivo regeneration. There are, however, few examples of bioengineered biomimetic corneal stroma. Here we describe the construction of an orthogonally oriented 3D corneal stroma model (3D-CSM) using pure electro-compacted collagen (EC). EC films comprise aligned collagen fibrils and support primary human corneal stromal cells (hCSCs). Cell-laden constructs are analogous to the anatomical structure of native human cornea. The hCSCs are guided by the topographical cues provided by the aligned collagen fibrils of the EC films. Importantly, the 3D-CSM are biodegradable, highly transparent, glucose-permeable and comprise quiescent hCSCs. Gene expression analysis indicated the presence of aligned collagen fibrils is strongly coupled to downregulation of active fibroblast/myofibroblast markers α-SMA and Thy-1, with a concomitant upregulation of the dormant keratocyte marker ALDH3. The 3D-CSM represents the first example of an optimally robust biomimetic engineered corneal stroma that is constructed from pure electro-compacted collagen for cell and tissue support. The 3D-CSM is a significant advance for synthetic corneal stroma engineering, with the potential to be used for full-thickness and functional cornea replacement, as well as informing in vivo tissue regeneration. STATEMENT OF SIGNIFICANCE: This manuscript represents the first example of a robust, transparent, glucose permeable and pure collagen-based biomimetic 3D corneal stromal model (3D-CSM) constructed from pure electro-compacted collagen. The collagen fibrils of 3D-CSM are aligned and orthogonally arranged, mimicking native human corneal stroma. The alignment of collagen fibrils correlates with the direction of current applied for electro-compaction and influences human corneal stromal cell (hCSC) orientation. Moreover, 3D-CSM constructs support a corneal keratocyte phenotype; an essential requirement for modelling healthy corneal stroma. As-prepared 3D-CSM hold great promise as corneal stromal substitutes for research and translation, with the potential to be used for full-thickness cornea replacement.

Donation of discarded ocular tissue in patients undergoing SMILE laser refractive surgery: developing appropriate guidelines.

Tissue Biobanks represent an invaluable resource. Despite the majority of people supporting tissue donation, the actual rate remains low overall. Tissue discarded from surgical procedures represents a further avenue for collection for use in research. We aim to understand the information and consent requirements in a cohort of healthy, post-ophthalmic surgical subjects to optimise future tissue collection in living donors. Patients attending an ophthalmic clinic following refractive surgery for myopia (SMILE) were identified. Patient consent was implied with the completion of the provided survey. The questionnaire included gender, age range and education status. The majority of 31 subjects identified a benefit for future patients as the main motive for potential donation of discarded tissue (71%). Payment for the discarded tissue would not influence their decision in 77.4%. Explanation of the potential benefits of research was the most important information to consider before making a decision to donate. Only 12.9% of patients would have refused to include further information. Almost half of patients felt that the Biobank became the owner of tissue following donation. Current surgical patients may be more inclined to participate in research than the general public because of a sense of duty or an increased understanding of the role of research in evolving treatment. Despite minor uncertainty about the eventual use of the tissue and data, most subjects were positive to donation of discarded ocular tissue and de-identified information. Consent and education processes should be revised within an ophthalmic practice to minimise future patient anxiety.