HYALURONAN

Hyaluronan is a naturally occurring substance in the body that retains moisture by binding over a thousand times its weight in water, making it essential for skin hydration and elasticity.
As we age, the natural production of Hyaluronan decreases, leading to reduced skin volume, hydration, and increased wrinkles.
Hyaluronan is widely used in skincare products for its ability to keep skin supple and hydrated, and is also utilized in medical treatments for joint pain and wound healing.

CAS Number: 9004-61-9
EC Number: 232-678-0
Chemical Formula: (C14H21NO11)n
Molecular Weight: 425.38 g/mol

Synonyms: HYALURONIC ACID SODIUM, acid hyaluronic, Hyaluronic acid powder, aluronic acid、HA, Hyaluronate Acid, HYALURONIC ACID (SODIUM HYALURONATE), Hyaluronic acid, bovine vitreous humor, Mucoitin, Sepracoat, hyaluronicaci, Hyaluronic Acid, MW 3,000, Hyaluronic Acid, MW 10,000, Hyaluronic Acid, MW 25,000, Hyaluronic Acid, MW 50,000, Hyaluronic Acid, MW 100,000, Hyaluronic Acid, MW 350,000, Hyaluronic Acid, MW 1,000,000, Hyaluronic Acid, MW 1,500,000, BP-29024, BP-29025, BP-29026, BP-29027, BP-29028, BP-29029, BP-29030, BP-29031, Hyaluronic acid, 57282-61-8 [RN], Hyaluronate Tetrasaccharide, NAG-(3-1)GCU-(4-1)NAG-(3-1)GCU

Hyaluronan is a humectant a substance that retains moisture and Hyaluronan is capable of binding over one thousand times Hyaluronan weight in water.
Hyaluronan is naturally found in many areas of the human body, including the skin, eyes, and synovial fluid of the joints.
Hyaluronan used in beauty and skincare products is primarily made by bacteria in a lab via a process called biofermentation.

As we age, the production of key substances in the skin, including Hyaluronan (along with collagen and elastin) decreases.
As a result, our skin loses volume, hydration, and plumpness.

Hyaluronan is a natural substance found in the fluids in the eyes and joints.
Hyaluronan acts as a cushion and lubricant in the joints and other tissues.

Different forms of Hyaluronan are used for cosmetic purposes.
Hyaluronan might also affect the way the body responds to injury and help to decrease swelling.

People also commonly take Hyaluronan by mouth and apply Hyaluronan to the skin for UTIs, acid reflux, dry eyes, wound healing, aging skin, and many other conditions, but there is no good scientific evidence to support most of these other uses.

Hyaluronan is a gooey, slippery substance that your body produces naturally.
Scientists have found Hyaluronan throughout the body, especially in eyes, joints and skin.

Hyaluronan is often produced by fermenting certain types of bacteria.
Rooster combs (the red, Mohawk-like growth on top of a rooster’s head and face) are also a common source.

Hyaluronan (pronounced hi-ah-lew-ron-ic) acid also known as Hyaluronic acid or hyaluronate is a gooey, slippery substance that your body produces naturally.
Scientists have found Hyaluronan throughout the body, especially in eyes, joints and skin.

Hyaluronan (abbreviated HA; conjugate base hyaluronate), also called Hyaluronic acid, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues.
Hyaluronan is unique among glycosaminoglycans as Hyaluronan is non-sulfated, forms in the plasma membrane instead of the Golgi apparatus, and can be very large: human synovial Hyaluronan averages about 7 million Da per molecule, or about 20,000 disaccharide monomers, while other sources mention 3–4 million Da.

The average 70 kg (150 lb) person has roughly 15 grams of hyaluronan in the body, one third of which is turned over (i.e., degraded and synthesized) per day.

As one of the chief components of the extracellular matrix, Hyaluronan contributes significantly to cell proliferation and migration, and is involved in the progression of many malignant tumors.
Hyaluronan is also a component of the group A streptococcal extracellular capsule, and is believed to play a role in virulence.

Hyaluronan, derived from the name hyalos meaning glass, is found in the human body.
Hyaluronan is known for its structural ability to hold approximately a thousand times as much water as itself.

Thanks to this feature, Hyaluronan has an important place in the healthy movement of muscles and bones.
At the same time, the decrease in Hyaluronan in the structure of the skin, which is the largest organ of our body, can cause skin dryness and wrinkles.
Hyaluronan application for the skin is among Hyaluronans frequently used as anti-aging.

Hyaluronan occurs naturally in the body but can be produced from animal sources or bacteria.
Hyaluronan can be found in various forms such as powder, tablet and liquid for oral intake.

In addition, there are also cream, ointment and serum types to be applied to the skin.
Additionally, Hyaluronan can be recommended as eye drops to relieve eye dryness during eye surgery or contact lens use.

Hyaluronan may sound intimidating many of us wouldn't dream of putting acid on our faces but science shows us Hyaluronan brilliant in skincare.
Hyaluronan is a gel-like substance that has the unique ability to retain moisture.

In fact, our bodies produce Hyaluronan naturally to keep our skin soft and supple.
Hyaluronan also found in our eyes, joints, and connective tissue.
So Hyaluronan works wonderfully as an anti-aging component in face creams and serums, as the Hyaluronan can hold over 1,000 times Hyaluronan weight in water. 

Hyaluronan is a completely transparent, non-adhesive, water-soluble and grease-free acid mucopolysaccharide.
Hyaluronan molecular weight is between a few hundred thousand to millions, and Hyaluronan makes up the dermis layer of the skin.

Hyaluronan unique molecular structure and physicochemical properties has many important physiological functions inside the body, such as lubricating joints, adjusting vascular permeability, adjusting proteins, diffusing and transporting water electrolytes, and promoting wound healing.
Hyaluronan has a unique water retention effect and has the best known natural moisturizing properties, making Hyaluronan the ideal natural moisturizer.

Hyaluronan is an essential drug in ophthalmic “sticky surgeries”.
Hyaluronan is used in cataract surgery, in which Hyaluronan sodium salt remains in the anterior chamber to maintain depth in the anterior chamber and ensure a clear surgical view.

Hyaluronan reduces the occurences of postoperative inflammation and complications, thus improving the vision-correcting effects of the surgery.
Hyaluronan is also used in complicated retinol detachment surgery.

Hyaluronan has a low molecular weight and is considered the ideal natural moisturizing agent, so Hyaluronan is used as an additive in high-end makeup and as a moisturizer in creams, gels, lotions, masks, and serums.
Hyaluronan is also used medically as a moisturizer to improve moisture retention and lubrication, and Hyaluronan also expands capillaries and improves skin health.
For example, Hyaluronan with a low molecular weight can be used as a lubricant in surgeries (such as knee surgery), while those with high molecular weight can be used as surgical lubricant and as a substitute for vitreous in ophthalmic surgery.

Hyaluronan is a naturally occurring glycosaminoglycan found throughout the body’s connective tissue.
Glycosaminoglycans are simply long unbranched carbohydrates, or sugars, called polysaccharides.

Hyaluronan is the main component of what gives your skin structure, and is responsible for that plump and hydrated look.
Hyaluronan plays a pivotal role in the wound healing process, and decreases as we age making us more susceptible to sagging and wrinkles.

Hyaluronan 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.

Skin aging is a multifactorial process consisting of two distinct and independent mechanisms: intrinsic and extrinsic aging.

Youthful skin retains Hyaluronan turgor, resilience and pliability, among others, due to Hyaluronan high content of water.
Daily external injury, in addition to the normal process of aging, causes loss of moisture.

The key molecule involved in skin moisture is Hyaluronan that has unique capacity in retaining water.
There are multiple sites for the control of Hyaluronan synthesis, deposition, cell and protein association and degradation, reflecting the complexity of Hyaluronan metabolism.

The enzymes that synthesize or catabolize Hyaluronan and Hyaluronan receptors responsible for many of the functions of Hyaluronan are all multigene families with distinct patterns of tissue expression.
Understanding the metabolism of Hyaluronan in the different layers of the skin and the interactions of Hyaluronan with other skin components will facilitate the ability to modulate skin moisture in a rational manner.

There are 2 types of Hyaluronan:

Micro Molecular Hyaluronan:
In this type of Hyaluronan, the molecules consist of low-weight micro molecules.
With their micro size, they can penetrate down to the epidermis layer of the skin, penetrate under the skin and repair any damage there.

Micromolecular Hyaluronan can act under the tissue and moisturize the skin from within.
This type of molecule can promote the natural production of Hyaluronan under the skin.

Macro Molecular Hyaluronan:
This Hyaluronan can be described as high molecular weight.
Hyaluronan usually does not go under the skin.

Due to this feature, Hyaluronan can make repairs on the skin surface.
Additionally, Hyaluronan is effective in moisturizing the skin surface and gaining elasticity.

Uses of Hyaluronan:
Hyaluronan is a naturally derived, non immunogenic, non adhesive glycosaminoglycan that plays a prominent role in various wound healing processes, as Hyaluronan as Hyaluronan is naturally angiogenic when degraded to small fragments.
Hyaluronan promotes early inflammation which is critical for initiating wound healing, but then moderates later stages of the process, allowing matrix stabilization and reduction of long term inflammation.
Hyaluronan is a main source for pharmaceutical, medical and cosmetic application.

Hyaluronan is a glycosaminoglycan component.
Hyaluronan occurs naturally in the dermis.

Hyaluronan is thought to play a critical role in healthy skin by controlling the physical and biochemical characteristics of epidermal cells.
Hyaluronan also regulates general skin activity, such as water content, elasticity, and the distribution of nutrients.

Hyaluronan water-absorption abilities and large molecular structure allow the epidermis to achieve greater suppleness, proper plasticity, and turgor.
Hyaluronan is a natural moisturizer with excellent water-binding capabilities.

In a solution of 2 percent Hyaluronan and 98 percent water, the Hyaluronan holds the water so tightly that Hyaluronan appears to create a gel.
However, Hyaluronan is a true liquid in that Hyaluronan can be diluted and will exhibit a liquid’s normal viscous flow properties.

When applied to the skin, Hyaluronan forms a viscoelastic film in a manner similar to the way Hyaluronan holds water in the intercellular matrix of dermal connective tissues.
This performance and behavior suggests that Hyaluronan makes an ideal moisturizer base, allowing for the delivery of other agents to the skin.

Manufacturers claim that the use of Hyaluronan in cosmetics results in the need for much lower levels of lubricants and emollients in a formulation, thereby providing an essentially greaseless product.
Furthermore, Hyaluronan ability to retain water gives immediate smoothness to rough skin surfaces and significantly improves skin appearance.
For the benefits of Hyaluronan to be realized in a cosmetic, Hyaluronan needs to be applied on a regular basis as Hyaluronan is broken down in skin within 24 to 48 hours of application.

Some people use Hyaluronan to promote skin health and fight signs of aging.
Hyaluronan may help wounds heal, too.

Some doctors also use Hyaluronan to relieve joint pain in people with arthritis.

The skin contains about half of the Hyaluronan in the body. 
Hyaluronan binds to water molecules, which helps keep the skin hydrated and supple.

Levels of Hyaluronan in the skin significantly decrease as people age, which can lead to dehydrated skin and wrinkles.
Taking Hyaluronan or using cosmetic products that contain Hyaluronan may improve skin hydration and reduce signs of aging.

Use for Animal Health of Hyaluronan:
Hyaluronan is used in treatment of articular disorders in horses, in particular those in competition or heavy work.
Hyaluronan is indicated for carpal and fetlock joint dysfunctions, but not when joint sepsis or fracture are suspected.

Hyaluronan is especially used for synovitis associated with equine osteoarthritis.
Hyaluronan can be injected directly into an affected joint, or intravenously for less localized disorders.

Hyaluronan may cause mild heating of the joint if directly injected, but this does not affect the clinical outcome.
Intra-articularly administered medicine is fully metabolized in less than a week.

According to Canadian regulation, hyaluronan in HY-50 preparation should not be administered to animals to be slaughtered for horse meat.
In Europe, however, the same preparation is not considered to have any such effect, and edibility of the horse meat is not affected.

Medical uses:
Hyaluronan 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 Hyaluronan could possibly cause adverse effects.
A 2020 meta-analysis found that intra-articular injection of high molecular weight Hyaluronan improved both pain and function in people with knee osteoarthritis.

Hyaluronan has been used to treat dry eye.
Hyaluronan is a common ingredient in skin care products.

Hyaluronan is used as a dermal filler in cosmetic surgery.
Hyaluronan 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, Hyaluronan is used as a soft tissue filler due to Hyaluronan 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, Hyaluronan fillers can result in a granulomatous foreign body reaction.

Uses Area of Hyaluronan:
Hyaluronan is a remarkable substance because of all the benefits and uses Hyaluronan has in your body.

Here are just a few of the benefits of Hyaluronan:
Hyaluronan helps things move smoothly.
Hyaluronan helps your joints work like a well-oiled machine.

Hyaluronan prevents pain and injury from bones grinding against each other.
Hyaluronan helps keep things hydrated.

Hyaluronan is very good at retaining water.
A quarter-teaspoon of Hyaluronan holds about one and a half gallons of water.

That’s why Hyaluronan is often used for treating dry eyes.
It’s also used in moisturizing creams, lotions, ointments and serums.

Hyaluronan makes your skin flexible.
Hyaluronan helps skin stretch and flex and reduces skin wrinkles and lines.
Hyaluronan is also proven to help wounds heal faster and can reduce scarring.

Sources of Hyaluronan:
Hyaluronan is produced on a large scale by extraction from animal tissues, such as chicken comb, and from Streptococci.

Benefits of Hyaluronan:

Promotes healthier, more supple skin:
Hyaluronan supplements can help your skin look and feel more supple.
Hyaluronan is a compound found naturally in the skin, where Hyaluronan binds to water to help retain moisture.

However, the natural aging process and exposure to things like ultraviolet radiation from the sun, tobacco smoke, and pollution can decrease Hyaluronan amounts in the skin.
Taking Hyaluronan supplements may prevent this decline by giving your body extra amounts to incorporate into the skin.

According to one 2014 study, doses of 120–240 milligrams (mg) per day for at least 1 month have been shown to significantly increase skin moisture and reduce dry skin in adults.
Hydrated skin also reduces the appearance of wrinkles, which may explain why several studies show that supplementing with Hyaluronan can make skin appear smoother.

When applied to the surface of the skin, Hyaluronan serums can reduce wrinkles, redness, and dermatitis.
Some dermatologists even inject Hyaluronan fillers to keep skin looking firm and youthful.

Can speed wound healing:
Hyaluronan also plays a key role in wound healing.
It’s naturally present in the skin, but Hyaluronan concentrations increase when there is damage in need of repair.

Hyaluronan helps wounds heal faster by regulating inflammation levels and signaling the body to build more blood vessels in the damaged area.
In some older studies, applying Hyaluronan to skin wounds has been shown to reduce the size of wounds and decrease pain faster than a placebo or no treatment at all.

Hyaluronan also has antibacterial properties, so Hyaluronan may help reduce the risk of infection when applied directly to open wounds.
What’s more, it’s effective at reducing gum disease, speeding up healing after tooth surgery, and eliminating ulcers when used topically in the mouth.

While the research on Hyaluronan serums and gels is promising, there has been no research to determine whether Hyaluronan supplements can provide the same benefits.
However, since oral supplements boost the levels of Hyaluronan found in the skin, it’s reasonable to suspect they may provide some benefit.

Relieve joint pain by keeping bones lubricated:
Hyaluronan is also found in the joints, where Hyaluronan keeps the space between your bones lubricated.
When the joints are lubricated, the bones are less likely to grind against each other and cause uncomfortable pain.

Hyaluronan supplements are very helpful for people with osteoarthritis, a type of degenerative joint disease caused by wear and tear on the joints over time.
Taking 80–200 mg daily for at least 2 months has been shown to significantly reduce knee pain in people with osteoarthritis, especially those between the ages of 40 and 70 years old.

Hyaluronan can also be injected directly into the joints for pain relief.
However, an analysis of over 21,000 adults found only a small reduction in pain and a greater risk of adverse effects.

Some research shows that pairing oral Hyaluronan supplements with injections can help extend pain-relieving benefits and increase the amount of time between shots.

Soothe acid reflux symptoms:
New research shows Hyaluronan supplements may help reduce symptoms of acid reflux.
When acid reflux occurs, the contents of the stomach are regurgitated up into the throat, causing pain and damage to the lining of the esophagus.

Hyaluronan may help soothe the damaged lining of the esophagus and speed up the recovery process.
One 2012 test-tube study found that applying a mixture of Hyaluronan and chondroitin sulfate to acid-damaged throat tissue helped Hyaluronan heal much faster than when no treatment was used.

Human studies have also shown benefits.
One study found that taking a Hyaluronan and chondroitin sulfate supplement along with an acid-reducing medication decreased reflux symptoms 60% more than taking acid-reducing medication alone.

Another older study showed that the same type of supplement was five times more effective at reducing acid reflux symptoms than a placebo.

Research in this area is still relatively new, and more studies are needed to replicate these results.
Nevertheless, these outcomes are promising.

Relieve dry eye and discomfort:
Approximately 11% older adults experience symptoms of dry eye due to reduced tear production or tears evaporating too quickly.
Since Hyaluronan is excellent at retaining moisture, it’s often used to treat dry eye.

Eye drops containing 0.2–0.4% Hyaluronan have been shown to reduce dry eye symptoms and improve eye health.
Contact lenses that contain slow-release Hyaluronan are also being developed as a possible treatment for dry eye.

In addition, Hyaluronan eye drops are frequently used during eye surgery to reduce inflammation and speed wound healing.
While applying them directly to the eyes has been shown to reduce dry eye symptoms and improve overall eye health, Hyaluronan is unclear whether oral supplements have the same effects.

One small study in 24 people found that combining topical and oral Hyaluronan was more effective at improving symptoms of dry eye than topical Hyaluronan alone.
However, more large, high-quality studies are needed to understand the effects of oral Hyaluronan supplements on eye health.

Preserve bone strength:
New animal research has begun to investigate the effects of Hyaluronan supplements on bone health.
Two older studies have found that Hyaluronan supplements can help slow the rate of bone loss in rats with osteopenia, the beginning stage of bone loss that precedes osteoporosis.

Some older test-tube studies have also shown that high doses of Hyaluronan can increase the activity of osteoblasts, the cells responsible for building new bone tissue.
While more high quality, recent research in humans is needed, early animal and test-tube studies are promising.

Could prevent bladder pain:
Approximately 3–6% of females suffer from a condition called interstitial cystitis, or painful bladder syndrome.
This disorder causes abdominal pain and tenderness, along with a strong and frequent urge to urinate.

While the causes of interstitial cystitis are unknown, Hyaluronan has been found to help relieve the pain and urinary frequency associated with this condition when inserted directly into the bladder through a catheter.
It’s unclear why Hyaluronan helps relieve these symptoms, but researchers hypothesize that Hyaluronan helps repair damage to bladder tissue, making Hyaluronan less sensitive to pain.

Studies have not yet determined whether oral Hyaluronan supplements can increase amounts of Hyaluronan in the bladder enough to have the same effects.

The benefits of Hyaluronan can be listed as follows:

Skin:
When Hyaluronan comes to Hyaluronan, the first thing that comes to mind is the skin.
Humidity decreases over time in the human body.

Lack of moisture can also cause wrinkles and other signs of aging, especially on the skin.
At this point, Hyaluronan has an important place in terms of giving the skin a vibrant appearance due to Hyaluronan water retention feature and ensuring the healing of wounds and skin blemishes.

Muscle and Joint:
Muscles and joints need intra-articular fluid to maintain their structural health.
Hyaluronan retains water and helps muscles and joints move smoothly and protects cartilage.

Eyelash:
Eye fluid naturally contains Hyaluronan.
Hyaluronan supports the natural health of the eye.

Hyaluronan is effective in protection.
At the same time, drops containing Hyaluronan may be recommended to treat dry eyes caused by lens use and some eye operations.

Although Hyaluronan has many benefits, a specialist should be consulted, especially in case of disease or damage.
A specialist doctor can recommend the form and treatment of Hyaluronan that is most suitable for the person.

Other Benefits:
anti-aging
moisturizing
wound healing
anti-wrinkle
increases skin elasticity
can treat eczema
can treat facial redness

Physiological Function of Hyaluronan:
Until the late 1970s, Hyaluronan was described as a "goo" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix.
For example, Hyaluronan is a major component of the synovial fluid and was found to increase the viscosity of the fluid.
Along with lubricin, Hyaluronan is one of the fluid's main lubricating components.

Hyaluronan is an important component of articular cartilage, where Hyaluronan is present as a coat around each cell (chondrocyte).
When aggrecan monomers bind to hyaluronan in the presence of HAPLN1 (Hyaluronan and proteoglycan link protein 1), large, highly negatively charged aggregates form.

These aggregates imbibe water and are responsible for the resilience of cartilage (Hyaluronan 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.

Hyaluronan is also a major component of skin, where Hyaluronan is involved in repairing tissue.
When skin is exposed to excessive UVB rays, Hyaluronan becomes inflamed (sunburn), and the cells in the dermis stop producing as much hyaluronan and increase the rate of Hyaluronan degradation.
Hyaluronan degradation products then accumulate in the skin after UV exposure.

While Hyaluronan is abundant in extracellular matrices, hyaluronan also contributes to tissue hydrodynamics, movement, and proliferation of cells and participates in a number of cell surface receptor interactions, notably those including Hyaluronan primary receptors, CD44 and RHAMM.
Upregulation of CD44 itself is widely accepted as a marker of cell activation in lymphocytes.

Hyaluronan's contribution to tumor growth may be due to Hyaluronan interaction with CD44.
Receptor CD44 participates in cell adhesion interactions required by tumor cells.

Although hyaluronan binds to receptor CD44, there is evidence hyaluronan degradation products transduce their inflammatory signal through toll-like receptor 2 (TLR2), TLR4, or both TLR2 and TLR4 in macrophages and dendritic cells.
TLR and hyaluronan play a role in innate immunity.

There are limitations including the in vivo loss of Hyaluronan limiting the duration of effect.

Over the past 2 decades there was considerable evidence presented that unraveled the functional role of Hyaluronan in molecular mechanisms and indicated the potential role of Hyaluronan for the development of novel therapeutic strategies for many diseases.

Functions of Hyaluronan include the following: hydration, lubrication of joints, a space filling capacity, and the framework through which cells migrate.
The synthesis of Hyaluronan increases during tissue injury and wound healing and Hyaluronan regulates several aspects of tissue repair, including activation of inflammatory cells to enhance immune response and the response to injury of fibroblasts and epithelial cells.

Hyaluronan also provides the framework for blood vessel formation and fibroblast migration that may be involved in tumor progression.
The correlation of Hyaluronan levels on the cell surface of cancer cells with the aggressiveness of tumors has also been reported.

The size of Hyaluronan appears to be of critical importance for Hyaluronan various functions described above.
Hyaluronan of high molecular size, usually in excess of 1,000 kDa, is present in intact tissues and is antiangiogenic and immunosuppressive, whereas smaller polymers of Hyaluronan are distress signals and potent inducers of inflammation and angiogenesis.

Wound repair:
As a major component of the extracellular matrix, Hyaluronan has a key role in tissue regeneration, inflammation response, and angiogenesis, which are phases of wound repair.
As of 2023, however, reviews of Hyaluronan 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 Hyaluronan may be beneficial for ulcer healing and may help to a small degree with pain control.
Hyaluronan combines with water and swells to form a gel, making Hyaluronan useful in skin treatments as a dermal filler for facial wrinkles; Hyaluronan 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.
Hyaluronan typically grows from the base of a wound and is able to fill wounds of almost any size Hyaluronan heals.

Hyaluronan is abundant in granulation tissue matrix.
A variety of cell functions that are essential for tissue repair may attribute to this Hyaluronan-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 Hyaluronan 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 Hyaluronan-rich extracellular matrix, which is regarded as a conducive environment for the migration of cells into this temporary wound matrix.

Hyaluronan 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 Hyaluronan and cell surface Hyaluronan receptors.
Hyaluronan 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 Hyaluronan.
Hyaluronan 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 Hyaluronan degradation or blocking Hyaluronan receptor occupancy.

By providing the dynamic force to the cell, Hyaluronan synthesis has also been shown to associate with cell migration.
Basically, Hyaluronan 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:
Hyaluronan plays an important role in the normal epidermis.
Hyaluronan also has crucial functions in the reepithelization process due to several of Hyaluronan properties.
These include being an integral part of the extracellular matrix of basal keratinocytes, which are major constituents of the epidermis; Hyaluronan free-radical scavenging function, and Hyaluronan role in keratinocyte proliferation and migration.

In normal skin, Hyaluronan is found in relatively high concentrations in the basal layer of the epidermis where proliferating keratinocytes are found.
CD44 is collocated with Hyaluronan in the basal layer of epidermis where additionally Hyaluronan has been shown to be preferentially expressed on plasma membrane facing the Hyaluronan-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 Hyaluronan in epidermis.
A report found Hyaluronan 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 Hyaluronan content, giving rise to increased tissue hydration.
Hyaluronan has been suggested that the free-radical scavenging property of Hyaluronan contributes to protection against solar radiation, supporting the role of CD44 acting as a Hyaluronan receptor in the epidermis.

Epidermal Hyaluronan 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, Hyaluronan is expressed in the wound margin, in the connective tissue matrix, and collocating with CD44 expression in migrating keratinocytes.

Receptors of Hyaluronan:
There is a variety of proteins that bind Hyaluronan, called hyaladherins, which are widely distributed in the ECM, the cell surface, the cytoplasm and the nucleus.
Those that attach Hyaluronan to the cell surface constitute Hyaluronan receptors.

The most prominent among these receptors is the transmembrane glycoprotein “cluster of differentiation 44” (CD44) that occurs in many isoforms, which are Hyaluronanss of a single gene with variable exon expression.
CD44 is found on virtually all cells, except red blood cells, and regulates cell adhesion, migration, lymphocyte activation and homing, and cancer metastasis.

The receptor for Hyaluronan-mediated motility (RHAMM) is another major receptor for Hyaluronan, and Hyaluronan is expressed in various isoforms.
RHAMM is a functional receptor in many cell types, including endothelial cells88 and in smooth muscle cells from human pulmonary arteries37 and airways.

The interactions of Hyaluronan with RHAMM control cell growth and migration by a complex network of signal transduction events and interactions with the cytoskeleton.
Transforming growth factor (TGF)-β1, which is a potent stimulator of cell motility, elicits the synthesis and expression of RHAMM and Hyaluronan, and thus initiates locomotion.

Structure of Hyaluronan:
Hyaluronan 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.
Hyaluronan can be 25,000 disaccharide repeats in length.

Polymers of Hyaluronan 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 Hyaluronan purified from human umbilical cord is 3,140,000 Da; other sources mention average molecular weight of 7 million Da for synovial fluid.
Hyaluronan also contains silicon, ranging 350–1,900 μg/g depending on location in the organism.

Hyaluronan is energetically stable, in part because of the stereochemistry of Hyaluronan component disaccharides.
Bulky groups on each sugar molecule are in sterically favored positions, whereas the smaller hydrogens assume the less-favorable axial positions.

Hyaluronan in aqueous solutions self-associates to form transient clusters in solution.
While Hyaluronan is considered a polyelectrolyte polymer chain, Hyaluronan does not exhibit the polyelectrolyte peak, suggesting the absence of a characteristic length scale between the Hyaluronan molecules and the emergence of a fractal clustering, which is due to the strong solvation of these molecules.

Biological Synthesis:
Hyaluronan is synthesized by a class of integral membrane proteins called Hyaluronic acid 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 Hyaluronan 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 Hyaluronan.

Hyaluronan 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.

Fasciacyte:
A fasciacyte is a type of biological cell that produces hyaluronan-rich extracellular matrix and modulates the gliding of muscle fasciae.

Fasciacytes are fibroblast-like cells found in fasciae.
They are round-shaped with rounder nuclei and have less elongated cellular processes when compared with fibroblasts.
Fasciacytes are clustered along the upper and lower surfaces of a fascial layer.

Fasciacytes produce hyaluronan, which regulates fascial gliding.

Biosynthetic Mechanism of Hyaluronan:
Hyaluronan is a linear glycosaminoglycan (GAG), an anionic, gel-like, polymer, found in the extracellular matrix of epithelial and connective tissues of vertebrates.
Hyaluronan is part of a family of structurally complex, linear, anionic polysaccharides.
The carboxylate groups present in the molecule make Hyaluronan negatively charged, therefore allowing for successful binding to water, and making Hyaluronan valuable to cosmetic and pharmaceutical products.

Hyaluronan consists of repeating β4-glucuronic acid (GlcUA)-β3-N-acetylglucosamine (GlcNAc) disaccharides, and is synthesized by hyaluronan synthases (HAS), a class of integral membrane proteins that produce the well-defined, uniform chain lengths characteristic to Hyaluronan.
There are three existing types of HASs in vertebrates: HAS1, HAS2, HAS3; each of these contribute to elongation of the Hyaluronan polymer.

For an Hyaluronan capsule to be created, this enzyme must be present because Hyaluronan polymerizes UDP-sugar precursors into Hyaluronan.
Hyaluronan precursors are synthesized by first phosphorylating glucose by hexokinase, yielding glucose-6-phosphate, which is the main Hyaluronan precursor.

Then, two routes are taken to synthesize UDP-n-acetylglucosamine and UDP-glucuronic acid which both react to form Hyaluronan.
Glucose-6-phosphate gets converted to either fructose-6-phosphate with hasE (phosphoglucoisomerase), or glucose-1-phosphate using pgm (α -phosphoglucomutase), where those both undergo different sets of reactions.

UDP-glucuronic acid and UDP-n-acetylglucosamine get bound together to form Hyaluronan via hasA (Hyaluronan synthase).

Synthesis of UDP-glucuronic acid:
UDP-glucuronic acid is formed from hasC (UDP-glucose pyrophosphorylase) converting glucose-1-P into UDP-glucose, which then reacts with hasB (UDP-glucose dehydrogenase) to form UDP-glucuronic acid.

Synthesis of N-acetyl glucosamine:
The path forward from fructose-6-P utilizes glmS (amidotransferase) to form glucosamine-6-P.
Then, glmM (Mutase) reacts with Hyaluronan to form glucosamine-1-P.
hasD (acetyltransferase) converts this into n-acetylglucosamine-1-P, and finally, hasD (pyrophosphorylase) converts Hyaluronan into UDP-n-acetylglucosamine.

Final step: Two disaccharides form Hyaluronan:
UDP-glucuronic acid and UDP-n-acetylglucosamine get bound together to form Hyaluronan via hasA (Hyaluronan synthase), completing the synthesis.

Chemistry and Physicochemical Properties of Hyaluronan:
Hyaluronan is a non-sulphated GAG and is composed of repeating polymeric disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine linked by a glucuronidic β (1→3) bond.
In aqueous solutions Hyaluronan forms specific stable tertiary structures.

Despite the simplicity in Hyaluronan composition, without variations in Hyaluronan sugar composition or without branching points, Hyaluronan has a variety of physicochemical properties.
Hyaluronan polymers occur in a vast number of configurations and shapes, depending on their size, salt concentration, pH, and associated cations.

Unlike other GAG, Hyaluronan is not covalently attached to a protein core, but Hyaluronan may form aggregates with proteoglycans.
Hyaluronan encompasses a large volume of water giving solutions high viscosity, even at low concentrations.

Degradation of Hyaluronan:
Hyaluronan can be degraded by a family of enzymes called hyaluronidases.
In humans, there are at least seven types of hyaluronidase-like enzymes, several of which are tumor suppressors.

The degradation products of hyaluronan, the oligosaccharides and very low-molecular-weight hyaluronan, exhibit pro-angiogenic properties.
In addition, recent studies showed hyaluronan fragments, not the native high-molecular weight molecule, can induce inflammatory responses in macrophages and dendritic cells in tissue injury and in skin transplant.

Hyaluronan can also be degraded via non-enzymatic reactions.
These include acidic and alkaline hydrolysis, ultrasonic disintegration, thermal decomposition, and degradation by oxidants.

Tissue and cell distribution of Hyaluronan:
Hyaluronan is widely distributed, from prokaryotic to eukaryotic cells.
In humans, Hyaluronan is most abundant in the skin accounting for 50% of the total body Hyaluronan the vitreous of the eye the umbilical cord and synovial fluid but Hyaluronan is also present in all tissues and fluids of the body, such as skeletal tissues heart valves the lung the aorta the prostate tunica albuginea, corpora cavernosa and corpus spongiosum of the penis.
Hyaluronan is produced primarily by mesenchymal cells but also by other cell types.

Etymology of Hyaluronan:
Hyaluronan is derived from hyalos (Greek for vitreous, meaning ‘glass-like’) and uronic acid because Hyaluronan was first isolated from the vitreous humour and possesses a high uronic acid content.
The term hyaluronate refers to the conjugate base of Hyaluronan.
Since the molecule typically exists in vivo in Hyaluronic acid polyanionic form, Hyaluronan is most commonly referred to as hyaluronan.

History of Hyaluronan:
Hyaluronan was first obtained by Karl Meyer and John Palmer in 1934 from the vitreous body in a cow's eye.
The first hyaluronan biomedical product, Healon, was developed in the 1970s and 1980s by Pharmacia, and approved for use in eye surgery (i.e., corneal transplantation, cataract surgery, glaucoma surgery, and surgery to repair retinal detachment).
Other biomedical companies also produce brands of hyaluronan for ophthalmic surgery.

Native Hyaluronan has a relatively short half-life (shown in rabbits) so various manufacturing techniques have been deployed to extend the length of the chain and stabilise the molecule for Hyaluronan use in medical applications.
The introduction of protein-based cross-links, the introduction of free-radical scavenging molecules such as sorbitol, and minimal stabilisation of the Hyaluronan chains through chemical agents such as NASHA (non-animal stabilised Hyaluronan) are all techniques that have been used to preserve Hyaluronan shelf life.

In the late 1970s, intraocular lens implantation was often followed by severe corneal edema, due to endothelial cell damage during the surgery.
Hyaluronan was evident that a viscous, clear, physiologic lubricant to prevent such scraping of the endothelial cells was needed.

The name "hyaluronan" is also used for a salt.

Research of Hyaluronan:
Due to Hyaluronan high biocompatibility and Hyaluronan common presence in the extracellular matrix of tissues, hyaluronan is used as a biomaterial scaffold in tissue engineering research.
In particular, research groups have found hyaluronan's properties for tissue engineering and regenerative medicine may be improved with cross-linking, producing a hydrogel.

Crosslinking may allow a desired shape, as well as to deliver therapeutic molecules into a host.
Hyaluronan can be crosslinked by attaching thiols (see thiomers)(trade names: Extracel, HyStem), hexadecylamides (trade name: Hymovis), and tyramines (trade name: Corgel).
Hyaluronan can also be crosslinked directly with formaldehyde (trade name: Hylan-A) or with divinylsulfone (trade name: Hylan-B).

Due to Hyaluronan ability to regulate angiogenesis by stimulating endothelial cells to proliferate in vitro, hyaluronan can be used to create hydrogels to study vascular morphogenesis.

Identifiers of Hyaluronan:
CAS Number: 
9004-61-9
31799-91-4 (potassium salt)
9067-32-7 (sodium salt)
ChEBI: CHEBI:16336
ECHA InfoCard: 100.029.695
EC Number: 232-678-0
UNII: S270N0TRQY
CompTox Dashboard (EPA): DTXSID90925319 DTXSID7046750, DTXSID90925319

EC / List no.: 232-678-0
CAS no.: 9004-61-9

CAS No.: 9004-61-9
Chemical Name: Hyaluronan
CBNumber: CB1176690
Molecular Formula: C14H22NNaO11
Molecular Weight: 403.31
MDL Number: MFCD00131348

Properties of Hyaluronan:
Chemical formula: (C14H21NO11)n
Solubility in water: Soluble (sodium salt)

storage temp.: −20°C
solubility: H2O: 5 mg/mL, clear, colorless
form: Lyophilized Powder
color: White
Odor: Odorless
Water Solubility: Soluble in water.
InChIKey: MAKUBRYLFHZREJ-IUPJJCKZNA-M
SMILES: [C@@H]1(O[C@H]2[C@H](O)[C@H]([C@H](O)O[C@@H]2C(=O)[O-])O)O[C@H](CO)[C@@H](O)C[C@H]1NC(=O)C.[Na+] |&1:0,2,3,5,6,9,15,18,21,r|
LogP: -6.623 (est)
CAS DataBase Reference: 9004-61-9
EWG's Food Scores: 1
FDA UNII: HYALURONIC ACID (NON-ANIMAL STABILIZED) (B7SG5YV2SI)
HYALURONIC ACID (S270N0TRQY)
NCI Drug Dictionary: hyaluronic acid
ATC code: D03AX05,M09AX01,R01AX09,S01KA01,S01KA51
EPA Substance Registry System: Hyaluronic acid (9004-61-9)

Molecular Weight: 425.38 g/mol
XLogP3-AA: -3.4
Hydrogen Bond Donor Count: 6
Hydrogen Bond Acceptor Count: 12
Rotatable Bond Count: 7
Exact Mass: 425.15332530 g/mol
Monoisotopic Mass: 425.15332530 g/mol
Topological Polar Surface Area: 194Ų
Heavy Atom Count: 29
Complexity: 576
Isotope Atom Count: 0
Defined Atom Stereocenter Count: 10
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Covalently-Bonded Unit Count: 1
Compound Is Canonicalized: Yes

Related compound of Hyaluronan:
D-Glucuronic acid and N-acetyl-D-glucosamine (monomers)

Names of Hyaluronan:

Regulatory process names:
Hyaluronic acid
Hyaluronic acid

IUPAC names:
(2S,3S,4S,5R,6R)-6-[(2S,3R,5S,6R)-3-acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid
(2Z,4S,4aS,5aR,12aS)-2-[amino(hydroxy)methylidene]-4,
[-4)GlcA(β1-3)GlcNAc(β1-]n
Hyaluronic acid
(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}

Other identifier:
9004-61-9