Collagen-based scaffolds with infused anti-VEGF release system as potential cornea substitute for high-risk keratoplasty: A preliminary in vitro evaluation

Currently the only widely accepted corneal blindness treatment is human donor cornea transplantation. However, increasing shortage of donor corneas as well as high risk of rejection in some corneal diseases remain two major problems, which limit the success of corneal transplantation. Corneal neovascularization is considered as one of the main risk factors of graft failure. Different cell-free biosynthetic scaffolds fabricated from collagens or collagen-like peptides are being tested as donor cornea substitutes (DCS). Here, we report for the first-time composite biosynthetic DCS with integrated sustained release system of anti-VEGF drug, bevacizumab and their preliminary in vitro validation. We have tethered gold nanoparticles with bevacizumab and integrated into a collagen-based cell-free hydrogel scaffold. Developed grafts preserved good optical properties and were confirmed not toxic to human corneal epithelial cells. Bevacizumab has been shown to constantly releasing from the DCS up to 3 weeks and preserved its anti-angiogenic properties. These results provide background for further use of infused composite biosynthetic DCS with integrated nanosystem of bevacizumab sustained release in corneal disease accompanied by neovascularisation where conventional corneal transplantation might fail

The Quest for Anti-inflammatory and Anti-infective Biomaterials in Clinical Translation.

Biomaterials are now being used or evaluated clinically as implants to supplement the severe shortage of available human donor organs. To date, however, such implants have mainly been developed as scaffolds to promote the regeneration of failing organs due to old age or congenital malformations. In the real world, however, infection or immunological issues often compromise patients. For example, bacterial and viral infections can result in uncontrolled immunopathological damage and lead to organ failure. Hence, there is a need for biomaterials and implants that not only promote regeneration but also address issues that are specific to compromised patients, such as infection and inflammation. Different strategies are needed to address the regeneration of organs that have been damaged by infection or inflammation for successful clinical translation. Therefore, the real quest is for multifunctional biomaterials with combined properties that can combat infections, modulate inflammation, and promote regeneration at the same time. These strategies will necessitate the inclusion of methodologies for management of the cellular and signaling components elicited within the local microenvironment. In the development of such biomaterials, strategies range from the inclusion of materials that have intrinsic anti-inflammatory properties, such as the synthetic lipid polymer, 2-methacryloyloxyethyl phosphorylcholine (MPC), to silver nanoparticles that have antibacterial properties, to inclusion of nano- and micro-particles in biomaterials composites that deliver active drugs. In this present review, we present examples of both kinds of materials in each group along with their pros and cons. Thus, as a promising next generation strategy to aid or replace tissue/organ transplantation, an integrated smart programmable platform is needed for regenerative medicine applications to create and/or restore normal function at the cell and tissue levels. Therefore, now it is of utmost importance to develop integrative biomaterials based on multifunctional biopolymers and nanosystem for their practical and successful clinical translation

Tendencies of globalization of development of international tourism

Проаналізовано сучасні тенденції розвитку міжнародного туризму як провідного сегмента світового ринку, однієї із найважливіших складових процесу глобалізації. Визначено передумови глобалізації світового туристичного ринку, окреслено перспективи розвитку системи міжнародного туризму в сучасних умовах. Зміст міжнародного туризму як економічної категорії представлено як функціональну спрямованість його впливу на формування сучасної глобальної економічної системи, що проявляється в єдності його функцій.In the article modern progress of international tourism trends are analysed as a leading world market segment, one of major constituents of process of globalization. Pre-conditions of globalization of world tourist market are certain, the prospects of development of the system of international tourism are outlined in modern terms. The table of contents of international tourism as an economic category is presented as a functional orientation of his influence on forming of the modern global economic system that shows up in unity of his functions. Passing of international tourism to the global stage of the development was caused by the specific of the market state of affairs of the concrete historical stage, aspiring of large tourist companies to minimization of prime price of tourist package and increase of guarantees of grant of the announced tourist services of the proper quality; and also by the height of investment attractiveness of tourist business as a result of mass character of international tourism and increase of effect of scale in him. Global international tourism certainly as the socio-economic phenomenon that depends already not on domestic, but from external factors, maintenance and quantity of that determined by a global world concord the members of that are related to each other in all spheres of public life, including an economy, policy, ideology, culture, social sphere, ecology, safety. By the basic components of globalization of international tourism following: expansion of international economic connections in a tourist production, increase of internationalization of factors of tourist production, distribution of multinationals corporations in tourist business

Organizational and informational model of analysis of the financial condition of credit union

Обґрунтовано актуальність проведення регулярного аналізу фінансового стану кредитних спілок як необхідного елемента підтвердження їх забезпеченості фінансовими ресурсами для подальшого ефективного ведення господарської діяльності. Доведено необхідність побудови організаційно-інформаційної моделі такого аналізу, яка включає мету і завдання, суб’єкти та об’єкти, систему показників, інформаційну базу, методичне забезпечення аналізу та прийоми узагальнення й реалізації його результатів. Метою аналізу фінансового стану кредитної спілки визначено своєчасне виявлення чинників, що спричиняють його погіршення, та розроблення заходів щодо усунення або мінімізації їх негативного впливу. До завдань аналізу фінансового стану кредитної спілки включено аналіз активів, пасивів, ліквідності, платоспроможності, ефективності та прибутковості. Суб’єктів аналізу фінансового стану кредитної спілки розподілено на зовнішніх та внутрішніх. До зовнішніх суб’єктів включено регулятора в особі Національного банку України; клієнтів; партнерів; фіскальні, судові органи; до внутрішніх – керівні органи, колегіальні й територіальні органи управління, працівників виконавчих підрозділів з функціями фінансового менеджменту. Основні показники аналізу фінансового стану кредитної спілки поділено на такі групи, як достатність капіталу, якість активів, ліквідність, ефективність і прибутковість та запропоновано алгоритм їх розрахунку відповідно до вимог правил складання й подання звітності учасниками ринку небанківських фінансових послуг, введених в дію з початку 2022 року. Окреслено інформаційну базу аналізу фінансового стану кредитних спілок як сукупності джерел внутрішньої та зовнішньої інформації, які включають фінансову та статистичну звітність, примітки до неї, а також оперативні дані фінансового обліку; показники діяльності кредитних спілок, що публікуються НБУ як в цілому по ринку, так і в розрізі установ на щоквартальній основі, а також інформацію про діяльність кредитних спілок, розміщену на сайтах саморегуючих організацій. Проведено огляд існуючих методик оцінювання фінансового стану кредитних спілок як його методичного забезпечення та визначено перспективним напрямком дослідження їх подальше удосконалення. Запропоновано заходи з підвищення фінансового стану кредитних спілок України.The relevance of conducting regular analysis of the financial condition of credit unions as a necessary element of confirming their financial resources for further effective business activities is substantiated. The necessity of building an organizational and information model of such analysis, which includes the purpose and objectives, subjects and objects, system of indicators, information base, methodological support of the analysis and methods of generalization and implementation of its results is proved. The purpose of the analysis of the financial condition of credit union is to identify in a timely manner the factors that cause its deterioration and develop measures to eliminate or minimize their negative impact. The tasks of the credit unionʼs financial condition analysis include the analysis of assets, liabilities, liquidity, solvency, efficiency and profitability. The subjects of the analysis of the financial condition of credit union are divided into external and internal. External entities include the regulator represented by the National Bank of Ukraine; customers; partners; fiscal, judicial authorities; internal ones – governing bodies, collegial and territorial governing bodies, employees of executive units with the functions of financial management. The main indicators of the analysis of the financial condition of credit union are divided into such groups as capital adequacy, asset quality, liquidity, efficiency and profitability and proposed an algorithm for calculating them are proposed in accordance with the requirements of the rules for preparing and submitting reports by participants of the non-bank financial services market, introduced since the beginning of 2022.The information base of the analysis of the financial condition of credit unions as a set of sources of internal and external information, which include financial and statistical reporting, as well as operational data of financial accounting; indicators of credit unions published by the NBU both in the market as a whole and by institutions on a quarterly basis, as well as information on the activities of credit unions posted on the websites of self-regulatory organizations are noted. The review of existing methods for assessing the financial condition of credit unions as its methodological support is carried out and promising area of research for their further improvement is identified. Measures to increase the financial condition of credit unions of Ukraine are proposed

LiQD Cornea: Pro-regeneration collagen mimetics as patches and alternatives to corneal transplantation

Transplantation with donor corneas is the mainstay for treating corneal blindness, but a severe worldwide shortage necessitates the development of other treatment options. Corneal perforation from infection or inflammation is sealed with cyanoacrylate glue. However, the resulting cytotoxicity requires transplantation. LiQD Cornea is an alternative to conventional corneal transplantation and sealants. It is a cell-free, liquid hydrogel matrix for corneal regeneration, comprising short collagen-like peptides conjugated with polyethylene glycol and mixed with fibrinogen to promote adhesion within tissue defects. Gelation occurs spontaneously at body temperature within 5 min. Light exposure is not required-particularly advantageous because patients with corneal inflammation are typically photophobic. The self-assembling, fully defined, synthetic collagen analog is much less costly than human recombinant collagen and reduces the risk of immune rejection associated with xenogeneic materials. In situ gelation potentially allows for clinical application in outpatient clinics instead of operating theaters, maximizing practicality, and minimizing health care costs

Phosphorylcholine and KR12-Containing Corneal Implants in HSV-1-Infected Rabbit Corneas

Severe HSV-1 infection can cause blindness due to tissue damage from severe inflammation. Due to the high risk of graft failure in HSV-1-infected individuals, cornea transplantation to restore vision is often contraindicated. We tested the capacity for cell-free biosynthetic implants made from recombinant human collagen type III and 2-methacryloyloxyethyl phosphorylcholine (RHCIII-MPC) to suppress inflammation and promote tissue regeneration in the damaged corneas. To block viral reactivation, we incorporated silica dioxide nanoparticles releasing KR12, the small bioactive core fragment of LL37, an innate cationic host defense peptide produced by corneal cells. KR12 is more reactive and smaller than LL37, so more KR12 molecules can be incorporated into nanoparticles for delivery. Unlike LL37, which was cytotoxic, KR12 was cell-friendly and showed little cytotoxicity at doses that blocked HSV-1 activity in vitro, instead enabling rapid wound closure in cultures of human epithelial cells. Composite implants released KR12 for up to 3 weeks in vitro. The implant was also tested in vivo on HSV-1-infected rabbit corneas where it was grafted by anterior lamellar keratoplasty. Adding KR12 to RHCIII-MPC did not reduce HSV-1 viral loads or the inflammation resulting in neovascularization. Nevertheless, the composite implants reduced viral spread sufficiently to allow stable corneal epithelium, stroma, and nerve regeneration over a 6-month observation period

Biomaterials-enabled cornea regeneration in patients at high risk for rejection of donor tissue transplantation

The severe worldwide shortage of donor organs, and severe pathologies placing patients at high risk for rejecting conventional cornea transplantation, have left many corneal blind patients untreated. Following successful pre-clinical evaluation in mini-pigs, we tested a biomaterials-enabled pro-regeneration strategy to restore corneal integrity in an open-label observational study of six patients. Cell-free corneal implants comprising recombinant human collagen and phosphorylcholine were grafted by anterior lamellar keratoplasty into corneas of unilaterally blind patients diagnosed at high-risk for rejecting donor allografts. They were followed-up for a mean of 24 months. Patients with acute disease (ulceration) were relieved of pain and discomfort within 1-2 weeks post-operation. Patients with scarred or ulcerated corneas from severe infection showed better vision improvement, followed by corneas with burns. Corneas with immune or degenerative conditions transplanted for symptom relief only showed no vision improvement overall. However, grafting promoted nerve regeneration as observed by improved touch sensitivity to normal levels in all patients tested, even for those with little/no sensitivity before treatment. Overall, three out of six patients showed significant vision improvement. Others were sufficiently stabilized to allow follow-on surgery to restore vision. Grafting outcomes in mini-pig corneas were superior to those in human subjects, emphasizing that animal models are only predictive for patients with non-severely pathological corneas; however, for establishing parameters such as stable corneal regeneration and nerve regeneration, our pig model is satisfactory. While further testing is merited, we have nevertheless shown that cell-free implants are potentially safe, efficacious options for treating high-risk patients

Collagen-Based Bioengineered Substitutes of Donor Corneal Allograft Implantation: Assessment and Hypotheses

To fabricate donor corneal substitutes based on carbodiimide cross-linked porcine collagen, to study their in vitro and in vivo properties, and to elaborate new implantation techniques for the donor corneal collagen-based substitutes, this study had been performed. Bioengineered substitutes of corneal stroma (BSCS) were fabricated by cross-linking porcine type I collagen with 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide and N-hydroxysuccinimide, as previously described. Their refractive indices were measured using an Abbe refractometer. The mechanical properties were evaluated by their ability to tolerate interrupted stitches placed during deep lamellar keratoplasty performed on isolated rabbit eyes. BSCS were then implanted into one cornea of 8 rabbits and were followed-up for 12 months. Our BSCS had refractive indices of 1.24-1.3 (human cornea 1.37-1.38), and tolerated the placement of 12 interrupted stitches well. A new technique, the BSCS “stitchless†implantation, was developed. When implanted into rabbit corneas, BSCS remained stably integrated and clear during the 12 month follow-up. Non-intensive opacities within corneal layers (grade 1.5 on a scale of 0 to 4) were observed in 2/8 eyes during the 1st postoperative week, and in one eye the opacity resolved. In the 2nd eye a fine opacity (grade 1) remained. Light microscopy confirmed the integrity of the implants and the absence of inflammation in corneal stroma. The current data suggest that the BSCS fabricated in the Ukraine by cross-linking collagen is a good alternative to human donor corneas if medical grade porcine collagen is used. In addition, the new “stitchless†technique of BSCS implantation may decrease corneal substitute damage and accelerate its epithelialisation