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Hyaluronic Acid in Pharmacology and Drug Delivery: A Review

Introduction

Hyaluronic acid (HA), also called hyaluronan, is a normally happening biodegradable mucopolysaccharide that is situated in mammals, bacteria, & most types of organisms. Hyaluronic acid has many natural functions, such as affect of cell differentiation and proliferation, rules of cell adhesion and motility, as well as supplying tissues various biochemical properties. HA also has many cell surface receptors (Disc44, ICAM-1, RHAMM) that allow it to effect multiple mobile processes, a few examples being morphogenesis, metastasis, wound repair, and inflammation. Hyaluronan is a key component in the extracellular matrix and pericellular matrix of vertebrate tissues, but can also take place intracellularly. HA exists in practically all body fluids and tissues, but mainly in: connective muscle, synovial substance of the joints, virtuous humor of the eye, in the combs of chickens, and highly in the umbilical cord. The attention varies and is also shown in desk 1.

Table 1: Examples of HA in the body

HA can be an unbranched non-sulfated glycosaminoglycan consisting of repeating disaccharides, the two sugars being uronic acid and N-acetylglucosamine. Thousands of these disaccharides blended together constitute the HA backbone. In solution Hyaluronic acid forms into a polyanion that can crosslink with its self and also has a high affinity to bind with normal water which gives it high viscous properties. Using its viscous regularity, hydrophilicity, and biocompatibility HA is employed currently in cosmetic dermatology, osteoarthritis treatments, and ophthalmology. It is also being analyzed as a appealing medicine delivery agent through various routes of your body, such as pulmonary, nasal, ophthalmic, parenteral, and topical ointment.

History

Hyaluronic acid was uncovered in 1934 by Karl Meyer and John Palmer by isolating an unfamiliar chemical substance from the vitreous humor of an bovine's eyes. This unknown substance they found was composed of two sugar substances, with one being uronic acid. The name originates from "hyalos" the Greek word for wine glass and uronic acid hence the name hyaluronic acid. It was later used commercially in 1942 by Endre Balazs who branded its use as substitution for egg whites in cooked goods. It wasn't medically used until the late 1950's by optometrist as a vitreous humor replacing during eye surgeries. They obtained this hyaluronan from human being umbilical cords and from the combs of roosters. The chemical framework of HA was settled in the 1950's by Karl Mayer and his research team first as an acid but under natural physiological conditions they found sodium like behaviors in the form of sodium hyaluronate. It had been not until around 1990 that the physiochemical structural properties and its uses in the body for medicine delivery were studied by multiple labs throughout the united states, which is still being looked into today.

Physicochemical and structural properties

Chemical Structure

Hyaluronic acid is made from an extremely energetically steady disaccharide that comprises a D-Glucuronic acid and N-acetylglucosamine destined along through alternating beta-1, 4 and beta-1, 3 glycosidic bonds. These individual disaccharides bind along to create a helical chain framework of varying span and molecular weight differing from 10 kDa to 1000 kDa and calculating up to 10 nm in length. With such versatile molecular weights comes different viscoelastic properties and uses in pharmacology.

Figure 1: Hyaluronic Acid Chemical substance structure.

Solution Structure

The HA polymer chain expands into a random coil when made in solution and displays unique rheological properties such to be extremely hydrophilic, as well as very lubricious. These different properties can possibly be described by crosslinking of these hyaluronan polymer chains even at very low concentrations. At higher concentrations and molecular weights, solutions form into very viscous jellies and hydrogels. Hydrogels are pseudo-plastic materials that contain very high shear-dependent properties, with the answer being a gel in normal conditions but when applied under great pressure flows easily, which makes HA in solution an extremely ideal lubricant. Also Hyaluronic acid varieties into a linear polyanion in solution, which stiffens the helical development, allows the chains to self-associate, and gives HA its hydrophilic properties. Allowing it to capture up to 1000 times its own weight in drinking water.

Biological properties

Hyaluronan plays many structural jobs throughout the extracellular matrix by non-specific and specific interactions. It has a stabilizing impact when destined to proteins, and is also important in cellular signaling transduction with specific substances and receptors. Some examples of receptors and substances are; versican, aggrecan, neurocan, Disc44, RHAMM, GHAp, LYVE-1, and TSG6. However the major receptor from current research is Disc44, because of its multifunctional cell surface glycoprotein that can be observed on many cell types. HA is also important in gene appearance of endothelial skin cells, eosinophils, macrophages, and some epithelial cells. Only low molecular weight Ha particles have a role in gene expression, varying in proportions from 20 kDa to 450 kDa. Furthermore to gene expression HA is also important in restoration and scar formation. When higher molecular weight molecules were within a recovery wound less scarring cells was observed than a wound in the presence of lower molecular weight HA. These results show how molecular weight is significant in the potency of the healing process and scaring. It has also been found that High molecular weight HA supports muscle integrity, and small HA fragments initiate an inflammatory response during an injury.

Synthesis of hyaluronic acid

Hyaluronic acid is glycosaminoglycan that happen to be most commonly synthesized in the skin cells Golgi body and secreted by keratinocytes, fibroblasts, or chondrocytes. The vital membrane proteins that synthesize HA are HAS1, HAS2, and HAS3(). With HAS position for hyaluronan synthase. These enzymes synthesize long, linear polymers made up of duplicating disaccharides components. The mechanism of HAS will involve chain extension by adding alternating monosaccharides of Glucuronic acid and N-acetylglucosamine before desired span is met and can reach up to 10, 000 repeating disaccharides with a molecular weight of 4 million Daltons(). In epidermis tissue and cartilage HA makes up a large ratio of the structure mass, so the synthesis in these locations is very high.

Degradation

The degradation of Hyaluronan is mediated by three types of enzymes in mammals: Hyaluronidase, b-D-glucuronidase, and beta-N-acetyl-hexosaminidase. Hyaluronidase reduces larger measured HA substances into smaller fragments, whereas the other two enzymes cleave the HA fragments by firmly taking away nonreducing terminal sugars or removing solo monosaccharides from the HA backbone(). Degradation can also appear in non-enzymatic reactions. A few examples are shear stress or thermal mechanisms, but can be also be divided by chemical substance reactions such as hydrolysis and degrading oxidants. Hyaluronan can also be degraded by ultrasonication as it can be applied shear stress in a non-random way(). Research demonstrates higher molecular weight chains degrade slower by ultrasonication than smaller duration Ha Chains. Furthermore, as temperature rise, stress on HA chains cause degradation and reduced viscosity as a function of temperature(). Hydrolysis of HA can occur as well in a arbitrary process but often breaking down greater chains into disaccharide fragments. Finally, Reactive oxygen types can be made by a cell from aerobic respiration. A few examples that degrade HA chains are hydroxyl radicals, aerobic respiration, and hypochloride.

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