Distribution, biological and structural functions
Hyaluronic acid is one of the fundamental elements of the extracellular matrix, because it is an important component of proteoglycans organization. It is the main anatomo-functional element of connective tissue and thus it is to be found ubiquitously in most of the tissues and organs, from skin to mucosa. The extracellular matrix of the skin is composed of hyaluronic acid and other glycosaminoglycans combined with collagen and elastin. In fact, human skin contains on average about 2565 mg of hyaluronic acid for 100 g of tissue and about 55% of glycosaminoglycans of the fundamental substance is represented by hyaluronic acid. The big quantity of water retained in the extracellular matrix thanks to the presence of hyaluronic acid gives softness, smoothness and elasticity to skin and mucosa.
Internal organs which are particularly rich in hyaluronic acid are intestine (villi and lamina propria) , organs of genitourinary system (vagina, ovaries especially ovarian follicles , endometrial epithelium and bladder in women, as well as connective tissue of erectile organ and bladder in men) , membranes next to cartilaginous tissues (ear, larynx and joints) [4,5], synovial fluid, vitreous humour, fetal membranes and umbilical cord [6,7], healing wounds  and every tissue rich in connective.
Within the fundamental substance of the connective, hyaluronic acid is free or associated with other glycosaminoglycans and with proteins to form macromolecular aggregates known as proteoglycans. In these macromolecules, hyaluronic acid is the supporting structure which, through binding proteins, maintains bound various glycosaminoglycans.
Hyaluronic acid of connective does not represent a structural component only, but it takes part in several functions of the tissue itself. In fact, it guarantees tenacity, tone, trophism and elasticity to tissue which also depend on the vitality of cellular, fibrillar and vascular structures which are to be found in the fundamental substance. Moreover, hyaluronic acid interacts with water and it forms a highly dispersed molecular network which is indispensable for the selective diffusion of soluti and trophic substances.
The fundamental substance of connective is in continuous renewal and there is a dynamic balance between synthesis of hyaluronic acid due to fibroblasts and its degradation due to hyaluronidase.
From a biological point of view, hyaluronic acid can associate with collagen, fibrin and other molecules of extracellular matrix. Initial response to a tissue damage is the creation of a temporary matrix, extremely rich in hyaluronic acid and fibrin, which supports the migration of fibroblasts and endothelial cells to the wound area [8,9].
Physical chemical characteristics and biological role of hyaluronic acid in tissue repair
Many biological processes mediated by hyaluronic acid are fundamental in tissue repair and wound healing [10,11].
Regenerating tissues are rich in hyaluronic acid because it contributes to a lot of cell functions which are essential for tissue repair: inflammation response, cell migration, proliferation and organization of extracellular matrix.
Whether hyaluronic acid is bound to cells or to components of extracellular matrix, its hydrophilic nature creates an environment which facilitates cell migration, thus promoting the process of wound repair. In fact, hygroscopicity in cutaneous tissue has a fundamental importance on regulating tissue hydration, especially during changing periods such as embryonic development [7,12,13,14,15] or during inflammatory processes secondary to tissue damage [16,17,18,19,20], moments in which there are high levels of hyaluronic acid. In fact, many studies have shown that tissue repair processes which occur in fetus are basically different from those of adults: hyaluronic acid concentration increases physiologically, inflammatory component is very low and collagen deposition is more efficacious and rapid . To create areas in which hydration is increased causes a weakening of cell anchorage to the extracellular matrix, thus promoting a temporary detachment which facilitates the processes of cell migration and division [14,21]. Moreover, hyaluronic acid, which is particularly present in pericellular area of matrix, can help to delay virus and bacteria penetration thanks to its particularly viscous nature .
Thanks to its hygroscopic, rheological and viscoelastic properties, hyaluronic acid can have an effect on cell functions by changing macro- and micro-environment, through its complex interactions with cells and other components of the extracellular matrix. In addition, hyaluronic acid and its oligoshaccarides can directly have an effect on cell functions including cell migration.
Finally, hyaluronic acid can function as scavenger of free radicals, as well as antioxidant. Within the inflammatory process, hyaluronic acid has a modulating effect, due to action on free radicals [23,24,25], as well as to an antioxidant action  and to the exclusion of lytic enzymes from immediate cellular environment and from other components of the extracellular matrix [25,27].
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