HYALURONIC ACID
Hyaluronic acid, also know as hyaluronan or hyaluronate, is one of the most widely used active ingredients in cosmetic formulations.
In wound regeneration, Hyaluronic acid has mainly cosmetic applications.
Hyaluronic acid is used in cosmetic formulations in concentrations ranging from 0.2 to 1%.
The maximum concentration of NaHA in a body lotion is 2%.
Hyaluronic acid and its sodium and potassium salts are important cosmetic ingredients that are incorporated in moisturizing and anti-ageing products.
Additionally, products that contain HA represent only 5%, while more than 95% of the total products contain sodium hyaluronate.
Hyaluronic acid and its derivates are incorporated in a multitude of cosmetic products for eye contour, lips, facial, and neck care, anti-cellulite body care, or cosmetic color conditioning in different cosmetic categories: creams, lotions, serums, masks
Hyaluronic Acid, Sodium Hyaluronate and Potassium Hyaluronate enhance the appearance of dry or damaged skin by reducing flaking and restoring suppleness.
Hyaluronic Acid is also used to thicken the aqueous (water) portion of cosmetics and personal care products.
When a rate of 1 mg/cm2 of a product is applied, the contribution of hyaluronic acid is 0.02 mg/cm2 of skin.
In skin care formulations, hyaluronic acid can be used as a moisturizing component, because of its hydrophilic nature.
Using cosmetic products such as creams or lotions that contain Hyaluronic acid helps to moisturize the skin and to improve elasticity, thereby decreasing the depth of wrinkles.
Hyaluronic acid can help increase the moisture content in your skin, which can have various skin benefits, including reducing the appearance of wrinkles and improving wound healing, among others
Additionally, the occlusive properties given by Hyaluronic acid may allow the biologically active substances incorporated in cosmetics to persist in the skin layers and possibly make it easier for them to penetrate the epidermis.
According to previous studies, some cosmetic Hyaluronic acid products have been proven efficient in protecting the skin from UV irradiation.
At the same time, sunscreen products containing hyaluronic acid help to maintain a firmer skin, protecting it from the injurious impact of UV radiation, due to the potential antioxidant effect of Hyaluronic acid.
In cosmetic formulations, hyaluronic acid has the function of a viscosity modifier and/or a skin conditioning agent.
Hyaluronic acid is mainly used in anti-ageing cosmetic products.
Low Molecular weight-hyaluronic acid has the ability to enhance the level of moisture of the skin and expedite regeneration.
High Molecular weight-hyaluronic acid forms a viscoelastic film when applied onto the skin and has a moisturizing effect.
The main action of the High Molecular weight-hyaluronic acid polymer is film forming and it reduces evaporation of water from the skin and thus possessesan occlusive effect.
Hyaluronic acid is also of particular importance as a delivery system of active ingredients.
Currently, there are some commercially available formulations incorporating actives in different concentrations.
These products are designated for the topical treatment of actinic keratosis and skin inflammatory diseases.
It has been proven that Hyaluronic acid enhances the penetration of the active ingredient through the stratum corneum (SC), which behaves as a barrier to the entry of the molecule into the deeper layers of the skin, and the holding and locating the active ingredient in the epidermis.
Topical preparations containing Hyaluronic acid in formulation are used for their healing properties, decreasing the skin irritation.
A topical preparation that contains Hyaluronic acid (0.2% w/w sodium hyaluronate (NaHA)) as a main component is currently available for the amelioration of acute and chronic wounds (areas of grafted skin, post-surgical incisions, etc.).
A significant number of in vitro and in vivo studies have shown the effectiveness of Hyaluronic acid treatment as: anti-inflammatory, skin regeneration and chondro-protective effect, anti-ageing and immunosuppressive effects, etc.
Hyaluronic acid is a glycosaminoglycan constituted from two disaccharides (N-acetylglucosamine and D-glucuronic acid), isolated initially from the vitreous humour of the eye, and subsequently discovered in different tissues or fluids (especially in the articular cartilage and the synovial fluid).
Hyaluronic acid is a polysaccharide belonging to the glycosaminoglycans, made up of disaccharide units constituted of N-acetylglucosamine and D-glucuronic acid.
Hyaluronic acid is a component of the connective, epithelial, and neural tissues and it represents a substantial constituent of the extracellular matrix
Hyaluronic acid is ubiquitous in vertebrates, including humans, and it is involved in diverse biological processes, such as cell differentiation, embryological development, inflammation, wound healing, etc.
Hyaluronic acid has many qualities that recommend it over other substances used in skin regeneration, with moisturizing and anti-ageing effects.
Hyaluronic acid molecular weight influences its penetration into the skin and its biological activity.
Considering that, nowadays, hyaluronic acid has a wide use and a multitude of applications (in ophthalmology, arthrology, pneumology, rhinology, aesthetic medicine, oncology, nutrition, and cosmetics), the present study describes the main aspects related to its use in cosmetology.
The biological effect of Hyaluronic acid on the skin level and its potential adverse effects are discussed.
Hyaluronic acid is a natural substance found in the fluids in the eyes and joints.
Hyaluronic acid acts as a cushion and lubricant in the joints and other tissues.
Among the many biological effects, Hyaluronic acid is involved in cell differentiation, embryological development, inflammation, wound healing, viscoelasticity, etc.
IUPAC name: (1→4)-(2-Acetamido-2-deoxy-D-gluco)-(1→3)-D-glucuronoglycan
Systematic IUPAC name: Poly{[(2S,3R,4R,5S,6R)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxane-2,4-diyl]oxy[(2R,3R,4R,5S,6S)-6-carboxy-3,4-dihydroxyoxane-2,5-diyl]oxy}
CAS Number: 9004-61-9
31799-91-4 (potassium salt)
9067-32-7 (sodium salt)[ECHA]
EC Number: 232-678-0
EC / List no.: 232-678-0
CAS no.: 9004-61-9
Chemical formula: (C14H21NO11)n
Solubility in water: Soluble (sodium salt)
Different forms of hyaluronic acid are used for cosmetic purposes.
Hyaluronic acid might also affect the way the body responds to injury and help to decrease swelling.
Hyaluronic acid (abbreviated HA; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues.
Physiological function
Until the late 1970s, hyaluronic acid was described as a "goo" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix.
For example, hyaluronic acid is a major component of the synovial fluid and was found to increase the viscosity of the fluid.
Along with lubricin, it is one of the fluid's main lubricating components.
Hyaluronic acid is an important component of articular cartilage, where it is present as a coat around each cell (chondrocyte).
When aggrecan monomers bind to hyaluronan in the presence of HAPLN1 (hyaluronic acid and proteoglycan link protein 1), large, highly negatively charged aggregates form.
These aggregates imbibe water and are responsible for the resilience of cartilage (its resistance to compression).
The molecular weight (size) of hyaluronan in cartilage decreases with age, but the amount increases.
A lubricating role of hyaluronan in muscular connective tissues to enhance the sliding between adjacent tissue layers has been suggested.
A particular type of fibroblasts, embedded in dense fascial tissues, has been proposed as being cells specialized for the biosynthesis of the hyaluronan-rich matrix.
Their related activity could be involved in regulating the sliding ability between adjacent muscular connective tissues.
Hyaluronic acid is also a major component of skin, where it is involved in repairing tissue.
When skin is exposed to excessive UVB rays, it becomes inflamed (sunburn), and the cells in the dermis stop producing as much hyaluronan and increase the rate of its degradation. Hyaluronan degradation products then accumulate in the skin after UV exposure.
A joint hydration supplement that uses hyaluronic acid
Wound repair
As a major component of the extracellular matrix, hyaluronic acid has a key role in tissue regeneration, inflammation response, and angiogenesis, which are phases of wound repair.
As of 2023, however, reviews of its effect on healing for chronic wounds including burns, diabetic foot ulcers or surgical skin repairs show either insufficient evidence or only limited positive clinical research evidence.
There is also some limited evidence to suggest that hyaluronic acid may be beneficial for ulcer healing and may help to a small degree with pain control.
Hyaluronic acid combines with water and swells to form a gel, making it useful in skin treatments as a dermal filler for facial wrinkles; its effect lasts for about 6 to 12 months, and treatment has regulatory approval from the US Food and Drug Administration.
Granulation
Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds.
It typically grows from the base of a wound and is able to fill wounds of almost any size it heals.
Hyaluronic acid is abundant in granulation tissue matrix.
A variety of cell functions that are essential for tissue repair may attribute to this HA-rich network.
These functions include facilitation of cell migration into the provisional wound matrix, cell proliferation, and organization of the granulation tissue matrix.
Initiation of inflammation is crucial for the formation of granulation tissue; therefore, the pro-inflammatory role of HA as discussed above also contributes to this stage of wound healing.
Cell migration
Cell migration is essential for the formation of granulation tissue.
The early stage of granulation tissue is dominated by a HA-rich extracellular matrix, which is regarded as a conducive environment for the migration of cells into this temporary wound matrix.
Hyaluronic acid provides an open hydrated matrix that facilitates cell migration, whereas, in the latter scenario, directed migration and control of related cell mechanisms are mediated via the specific cell interaction between Hyaluronic acid and cell surface Hyaluronic acidreceptors.
It forms links with several protein kinases associated with cell locomotion, for example, extracellular signal-regulated kinase, focal adhesion kinase, and other non-receptor tyrosine kinases.
During fetal development, the migration path through which neural crest cells migrate is rich in HA. HA is closely associated with the cell migration process in granulation tissue matrix, and studies show that cell movement can be inhibited, at least partially, by Hyaluronic acid degradation or blocking HA receptor occupancy.
By providing the dynamic force to the cell, Hyaluronic acid synthesis has also been shown to associate with cell migration.
Basically, Hyaluronic acid is synthesized at the plasma membrane and released directly into the extracellular environment.
This may contribute to the hydrated microenvironment at sites of synthesis, and is essential for cell migration by facilitating cell detachment.
Skin healing
HA plays an important role in the normal epidermis. HA also has crucial functions in the reepithelization process due to several of its properties.
These include being an integral part of the extracellular matrix of basal keratinocytes, which are major constituents of the epidermis; its free-radical scavenging function, and its role in keratinocyte proliferation and migration.
In normal skin, Hyaluronic acid is found in relatively high concentrations in the basal layer of the epidermis where proliferating keratinocytes are found.
CD44 is collocated with Hyaluronic acid in the basal layer of epidermis where additionally it has been shown to be preferentially expressed on plasma membrane facing the
Hyaluronic acid-rich matrix pouches.
Maintaining the extracellular space and providing an open, as well as hydrated, structure for the passage of nutrients are the main functions of
Hyaluronic acid in epidermis.
A report found Hyaluronic acid content increases in the presence of retinoic acid (vitamin A).
The proposed effects of retinoic acid against skin photo-damage and photoaging may be correlated, at least in part, with an increase of skin Hyaluronic acid content, giving rise to increased tissue hydration.
It has been suggested that the free-radical scavenging property of HA contributes to protection against solar radiation, supporting the role of CD44 acting as a HA receptor in the epidermis.
Epidermal HA also functions as a manipulator in the process of keratinocyte proliferation, which is essential in normal epidermal function, as well as during reepithelization in tissue repair.
In the wound healing process, HA is expressed in the wound margin, in the connective tissue matrix, and collocating with CD44 expression in migrating keratinocytes.
Medical uses
Hyaluronic acid has been FDA-approved to treat osteoarthritis of the knee via intra-articular injection.
A 2012 review showed that the quality of studies supporting this use was mostly poor, with a general absence of significant benefits, and that intra-articular injection of Hyaluronic acid could possibly cause adverse effects.
A 2020 meta-analysis found that intra-articular injection of high molecular weight HA improved both pain and function in people with knee osteoarthritis.
Hyaluronic acid has been used to treat dry eye.
Hyaluronic acid is a common ingredient in skin care products. Hyaluronic acid is used as a dermal filler in cosmetic surgery.
Hyaluronic acid is typically injected using either a classic sharp hypodermic needle or a micro-cannula.
Some studies have suggested that the use of micro-cannulas can significantly reduce vessel embolisms during injections.
Currently, hyaluronic acid is used as a soft tissue filler due to its bio-compatibility and possible reversibility using hyaluronidase.
Complications include the severing of nerves and microvessels, pain, and bruising.
Some side effects can also appear by way of erythema, itching, and vascular occlusion; vascular occlusion is the most worrisome side effect due to the possibility of skin necrosis, or even blindness in a patient.
In some cases, hyaluronic acid fillers can result in a granulomatous foreign body reaction.
Sources
Hyaluronic acid is produced on a large scale by extraction from animal tissues, such as chicken comb, and from Streptococci.
Structure
Hyaluronic acid is a polymer of disaccharides, which are composed of D-glucuronic acid and N-acetyl-D-glucosamine, linked via alternating β-(1→4) and β-(1→3) glycosidic bonds.
Hyaluronic acid can be 25,000 disaccharide repeats in length.
Polymers of hyaluronic acid can range in size from 5,000 to 20,000,000 Da in vivo.
The average molecular weight in human synovial fluid is 3–4 million Da, and hyaluronic acid purified from human umbilical cord is 3,140,000 Da; other sources mention average molecular weight of 7 million Da for synovial fluid.
Hyaluronic acid also contains silicon, ranging 350–1,900 μg/g depending on location in the organism.
Hyaluronic acid is energetically stable, in part because of the stereochemistry of its component disaccharides.
Bulky groups on each sugar molecule are in sterically favored positions, whereas the smaller hydrogens assume the less-favorable axial positions.
Hyaluronic acid in aqueous solutions self-associates to form transient clusters in solution.
While it is considered a polyelectrolyte polymer chain, hyaluronic acid does not exhibit the polyelectrolyte peak, suggesting the absence of a characteristic length scale between the hyaluronic acid molecules and the emergence of a fractal clustering, which is due to the strong solvation of these molecules.
Biological synthesis
Hyaluronic acid is synthesized by a class of integral membrane proteins called hyaluronan synthases, of which vertebrates have three types: HAS1, HAS2, and HAS3.
These enzymes lengthen hyaluronan by repeatedly adding D-glucuronic acid and N-acetyl-D-glucosamine to the nascent polysaccharide as it is extruded via ABC-transporter through the cell membrane into the extracellular space.
The term fasciacyte was coined to describe fibroblast-like cells that synthesize HA.
Hyaluronic acid synthesis has been shown to be inhibited by 4-methylumbelliferone (hymecromone), a 7-hydroxy-4-methylcoumarin derivative.
This selective inhibition (without inhibiting other glycosaminoglycans) may prove useful in preventing metastasis of malignant tumor cells.
There is feedback inhibition of hyaluronan synthesis by low-molecular-weight hyaluronan (<500 kDa) at high concentrations, but stimulation by high-molecular-weight hyaluronan (>500 kDa), when tested in cultured human synovial fibroblasts.
Bacillus subtilis recently has been genetically modified to culture a proprietary formula to yield hyaluronans, in a patented process producing human-grade product.
See also
Alguronic acid
Sodium hyaluronate
EC / List no.: 618-620-0
CAS no.: 9067-32-7
