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      Hyaluronic Acid in the Third Millennium

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          Abstract

          Since its first isolation in 1934, hyaluronic acid (HA) has been studied across a variety of research areas. This unbranched glycosaminoglycan consisting of repeating disaccharide units of N-acetyl- d-glucosamine and d-glucuronic acid is almost ubiquitous in humans and in other vertebrates. HA is involved in many key processes, including cell signaling, wound reparation, tissue regeneration, morphogenesis, matrix organization and pathobiology, and has unique physico-chemical properties, such as biocompatibility, biodegradability, mucoadhesivity, hygroscopicity and viscoelasticity. For these reasons, exogenous HA has been investigated as a drug delivery system and treatment in cancer, ophthalmology, arthrology, pneumology, rhinology, urology, aesthetic medicine and cosmetics. To improve and customize its properties and applications, HA can be subjected to chemical modifications: conjugation and crosslinking. The present review gives an overview regarding HA, describing its history, physico-chemical, structural and hydrodynamic properties and biology (occurrence, biosynthesis (by hyaluronan synthases), degradation (by hyaluronidases and oxidative stress), roles, mechanisms of action and receptors). Furthermore, both conventional and recently emerging methods developed for the industrial production of HA and its chemical derivatization are presented. Finally, the medical, pharmaceutical and cosmetic applications of HA and its derivatives are reviewed, reporting examples of HA-based products that currently are on the market or are undergoing further investigations.

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          Hyaluronan as an immune regulator in human diseases.

          Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on various cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage from the environment by interacting with TLR2 and TLR4. Hyaluronan and hyaluronan-binding proteins regulate inflammation, tissue injury, and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration. This review focuses on the role of hyaluronan as an immune regulator in human diseases.
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            Hyaluronidases: their genomics, structures, and mechanisms of action.

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              Hyaluronan in tissue injury and repair.

              A hallmark of tissue injury and repair is the turnover of extracellular matrix components. This review focuses on the role of the glycosaminoglycan hyaluronan in tissue injury and repair. Both the synthesis and degradation of extracellular matrix are critical contributors to tissue repair and remodeling. Fragmented hyaluronan accumulates during tissue injury and functions in ways distinct from the native polymer. There is accumulating evidence that hyaluronan degradation products can stimulate the expression of inflammatory genes by a variety of immune cells at the injury site. CD44 is the major cell-surface hyaluronan receptor and is required to clear hyaluronan degradation products produced during lung injury; impaired clearance of hyaluronan results in persistent inflammation. However, hyaluronan fragment stimulation of inflammatory gene expression is not dependent on CD44 in inflammatory macrophages. Instead, hyaluronan fragments utilize both Toll-like receptor (TLR) 4 and TLR2 to stimulate inflammatory genes in macrophages. Hyaluronan also is present on the cell surface of lung alveolar epithelial cells and provides protection against tissue damage by interacting with TLR2 and TLR4 on these parenchymal cells. The simple repeating structure of hyaluronan appears to be involved in a number of important aspects of noninfectious tissue injury and repair that are dependent on the size and location of the polymer as well as the interacting cells. Thus, the interactions between the endogenous matrix component hyaluronan and its signaling receptors initiate inflammatory responses, maintain structural cell integrity, and promote recovery from tissue injury.
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                Author and article information

                Journal
                Polymers (Basel)
                Polymers (Basel)
                polymers
                Polymers
                MDPI
                2073-4360
                25 June 2018
                July 2018
                : 10
                : 7
                : 701
                Affiliations
                Department of Life Sciences and Biotechnology, Master Course in Cosmetic Science and Technology (COSMAST), University of Ferrara, Via L. Borsari 46, 44121 Ferrara, Italy; arianna.fallacara@ 123456student.unife.it (A.F.); erika.baldini@ 123456student.unife.it (E.B.); vrs@ 123456unife.it (S.V.)
                Author notes
                [* ]Correspondence: smanfred@ 123456unife.it ; Tel.: +39-0532-455294; Fax: +39-0532-455378
                Author information
                https://orcid.org/0000-0002-2434-4727
                Article
                polymers-10-00701
                10.3390/polym10070701
                6403654
                30960626
                0a58df58-aef4-43b6-94a0-976a0bc68b62
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 May 2018
                : 20 June 2018
                Categories
                Review

                biological activity,crosslinking,drug delivery,cosmetic,food-supplement,functionalization,hyaluronan applications,hyaluronan derivatives,hyaluronan synthases,hyaluronic acid,hyaluronidases,physico-chemical properties

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