Hyaluronic Acid
Hyaluronsyre og dens natriumsalt Sodium Hyaluronate er vigtige komponenter i kroppen og findes næste over alt i kroppen.
The molecular weight is crucial for its properties. Overall, high molecular weight hyaluronic acid has anti-inflammatory and immunosuppressive properties and is involved in certain gene expressions, while low molecular weight hyaluronic acid has shown antioxidant, inflammatory and immunostimulatory properties.
A common property of hyaluronic acid with different molecular weights is an incredibly high water binding capacity by which it provides moisture and fullness to e.g. to the skin. Moisture is a very basic component of the skin and often part of the solution to maintain a nice and functional skin. The consequences of reduced moisture in the skin can be many - e.g. dry skin which has a poorer barrier and thus increased risk of infection. Dry skin also increases the risk of allergies and skin healing deteriorates when there is less moisture. In many skin problems there is correlation with lack of moisture. Older skin is also characterized by containing less moisture.
PUCA PURE & CARE anvender en Sodium Hyaluronate udvundet fra Steptococcus-bakterier. Det er en blanding af 10 % lavmolekylær vægt og 90 % mellemmolekylære vægt.
Produkter med HYALURONSYRE
HYALURONSYRE
A SIMPLE BUT INTERESTING CHEMICAL STRUCTURE
Hyaluronic acid is a naturally occurring glycosaminoglycan - a biopolymer of disaccharides with very special physical, chemical and biological properties. Its properties are highly dependent on the molecular weight, which can range from 10 to 1000 kDa (1). Thus, the name hyaluronic acid, or hyaluronan as it is also called, covers not only one molecule with one particular structure, but all the chain lengths that occur with this specific and repeating structure of the two sugar molecules D-glucuronic acid and N-acetyl-D-glucosamine - See Figure 1.
Da hyaluronsyre spænder over en så bred vifte af molekyler inddeler man dem ofte i nogle grupper baseret på deres molekylvægt. Der er ikke helt enighed om hvor grænserne for hver gruppe går, men det er nogenlunde som følger: 40-500 kDa er lavmolekylær vægt (LMW), 500-2000 kDa er mellemmolekylære vægt (MMW) og > 2000 kDa er højmolekylære vægt (HMW).
Strukturen af hyaluronsyre er en snoet kæde uden forgreninger og består af mellem 500 og 50.000 monosakkarider og måler op til 10 nm – dog normalt ca 1 nm (2). Det er relativt store molekyler. Til sammenligning er et hårstrå ca 80.000 til 100.000 nm i diameter.
Figur 1. Hyaluronsyre-strukturen. Her ses to enheder af disakkariderne der udgør hyaluronsyrens molekylære enhed. I venstre side af figuren ses en D-glucuronsyre, som er bundet til en N-acetylglucosamin med en 1→3 glykosid-binding. Denne N-acetylglucosamin er bundet til den næste d-glucuronsyre med en 1→4 glykosid-binding, som er bundet sammen med den sidste-acetylglucosamin i figuren via en 1→3 glykosid-binding. Det lille ”n” betyder at det kan være mange gentagelser af denne struktur.
Hyaluronsyre er i modsætning til de andre glycosaminoglycaner, som fx chondroitin sulphate, dermatan sulphate og heparin, ikke sulfateret – dvs der er ikke en sulfat-gruppe på og desuden er hyaluronsyre i modsætning til de andre glycosaminoglycaner ikke biosyntetiseret inde i cellens golgi-apparat, men af proteiner placeret i cellemembranen. Glycosaminoglycaner har mange forskellige funktioner i og omkring cellerne – fx medvirker nogle i regulering af cellevækst, kardannelse, forskellige neurologiske processer og infektion.
Navnet ”hyaluronan” blev introduceret i 1986 for at tilpasse det oprindelig navn, hyaluronsyre, til den polysakkaridnomenklartur som er gældende. Men i dag bruges ofte navnet hyaluronsyre – den tilsvarende natrium salt er natrium hyaluronat, hvor hydrogen-atomet i D-glucuronsyre-delen er udskiftet med natrium, som blot er løst bundet og dermed er molekylet på anion form – dvs den er negativt ladet. I kroppen er hyaluronsyre primært på anion form. I INCI-nomenklatur er det ”Hyaluronic Acid” og ”Sodium Hyaluronate” og det er oftest disse to versioner der bruges i de mange anvendelser som hyaluronan har.
(1) kDa = kilo Dalton (1000 Da). Unit of mass, which corresponds to g / mol and is used to express how much a molecule weigh is. For example, one water molecule weighs about 18 Da.
(2) nm = nanometer. 1 nm = 0.0000001 cm
HYALURONSYRE
OCCURRENCE, BIOSYNTHESIS AND DEGRADATION
Hyaluronic acid was first isolated from cattle eyes in 1934 - today it is known that it is found almost everywhere in the human body, and it is the same structure that is found in most animals and even in some bacteria. The chemical structure of hyaluronic acid was identified in the 1950s.
The highest concentration of hyaluronic acid in humans is found in the eye and synovial fluid and cartilage, but the largest amount is found in the skin - here about 50% of the body hyaluronic acid is located, primarily in the dermis layer of the skin. More specifically, hyaluronic acid is found especially in the extracellular matrix around the cells, and constitutes a primary component together with, for example, collagen and other glycosaminoglycans in the supporting and protecting structures around the cells.
Something very special about hyaluronic acid is that it can bind a lot of water and is thus very important in terms of retaining moisture and fullness in the tissues. It has been discovered that in young skin it is mostly hyaluronic acid in "free form" which can bind a lot of water, while in older skin it is more bound to proteins and other structures and thus has less water-binding capacity.
A person weighing 70 kg contains about 15 g of hyaluronic acid and about 1/3 of this is converted every day - i.e. hyaluronic acid has a very high turnover: a large part is broken down and built up every day.
The biosynthesis of hyaluronic acid is controlled by Hyaluronan synthase proteins (abbreviated HAS), of which there are three types in mammals: HAS-1, HAS-2 and HAS-3, each of which synthesizes different lengths of hyaluronic acid. These proteins are transmembrane, which means that they are located in and span the entire thickness of the cell membrane. Here they make sure that the synthesis itself takes place on the inside of the cell while the growing chain eventually emerges on the outside of the cell.
Most cells in the body have the ability to synthesize hyaluronic acid. In the skin, it is primarily the fibroblasts that are responsible for the synthesis, which is increased by wound healing, for example.
Nedbrydningshastigheden af hyaluronsyre er ikke ens de forskellige steder i kroppen. Fx har hyaluronsyre en halveringstid på 2-5 minutter i blodet, ca 1 dag i huden, 1-3 uger i brusk og ca 10 uger i øjet. Nedbrydningsprocessen kan både være via enzymer og via frie radikaler (oxidation) – men det er svært at studere og man ved ikke helt hvordan fordeling er mellem disse to typer af processer. Enzymerne, som står for nedbrydningen, kaldes hyaluronidaser (forkortet HYAL) – der findes mindst 7 typer hyaluronidase-lignende enzymer, hvoraf HYAL-1 især findes i serum. Nedbrydningsprodukterne er oligosakkarider og lav-molekylær hyaluronsyre. Nedbrydningen via frie radikaler er en oxidationsproces som fx finder sted ved UV-påvirkning og ved lav og høj pH.
HYALURONSYRE
A MOLECULE WITH MANY FUNCTIONS IN THE BODY
Hyaluronsyre er meget hygroskopisk – dvs den har en meget stor kapacitet til at binde vand – og netop dette er en egenskab, som giver hyaluronsyre flere af dens funktioner. Man har målt at hyaluronsyre kan binde ca 1000 gange dens egen vægt i vand. Jo højere molekylvægt, jo højere er den vandbindende egenskab. Dette gør at hyaluronsyre er en meget god fugtbinder og idet den binder så meget vand giver det også volumen. Desuden giver den en smørende/lubrikerende effekt og viskositet. Blot 1 % hyaluronsyre i vand giver en ret viskøs gel med særlige reologiske egenskaber: Det er pseudo-plastisk og viskoelastisk, hvilket betyder, at viskositeten falder når gelen påføres stress eller pres og det har en vis elastisk evne, hvilket er vigtigt for dens lubrikerende, stabiliserede og stødabsorberende effekt. Fx i led og andre steder i kroppen hvor der er bevægelse er den lubrikerende effekt vigtig.
På celleniveau er hyaluronsyre med til at regulere migrationen af celler – den hydrerede matrix, som hyaluronsyre giver, facilitere cellemigration, hvilket er vigtig i rigtig mange processer i kroppen. Fx ved sårheling og ved dannelsen af nye blodkar og immunsystemet er meget afhængig af at celler kan bevæge sig rundt i vævene. Ligeså sker der en stor cellemigration ved cancerudvikling.
A number of studies have been carried out on the role of hyaluronic acid in the wound healing process, which is a very complex process, with many cellular and molecular "actors". The wound healing process can be divided into several (partially overlapping) phases: hemostasis, inflammation, cell proliferation and remodeling. The hemostasis is about stopping the bleeding - the blood coagulates. In the inflammation phase, the area is “cleansed”, which means damaged and dead cells and any external units (e.g. bacteria) are cleaned out. This phase includes, for example, white blood cells. Special growth factors are instrumental in starting the next phase:
Celle-proliferationen. Her vokser og deler celler sig så det udfylder vævet med de rette celler og der dannes nye blodkar med mere. Sidste fase – remodelering – går ud på at vævet ”modnes” og der sker ”justeringer. Fx udskiftes og omarrangeres noget af collagenet der er dannet, hvilket øger trækstyrken af vævet, og udtjente komponenter og celler fjernes.
There are particularly high concentrations of high molecular weight hyaluronic acid at the beginning of the healing process. The cells in the area will naturally synthesize more hyaluronic acid upon damage to the skin, where it forms a moist and gel-like medium in which the various cells can more easily migrate. Gradually, hyaluronic acid is broken down by hyaluronidase, which is secreted by the cells that migrate into the medium. This results in hyaluronic acid of smaller molecular weight, which promotes inflammation and blood vessel formation. In this way, hyaluronic acid plays different roles in the wound healing process and helps to control the phases.
Low molecular weight hyaluronic acid has shown antioxidant, inflammatory and immunostimulatory properties, while high molecular weight hyaluronic acid is involved in certain gene expressions and has anti-inflammatory and immunosuppressive properties. In the dermis of the skin, it helps to regulate the water balance and stabilize the skin structure and stimulate collagen synthesis in fibroblasts.
Man ved også at hyaluronsyre kan binde visse receptorer – fx CD44, som findes på de fleste celletyper og er involveret i reguleringen af vedhæftning, migration, aktivering og differentiering af celler og cancer metastase-processen. CD44 er også med i regulering af hyaluronsyre-niveauet. En anden receptortype som hyaluronsyre kan binde er RHAMM, som også er medvirkende i celle-vækst og migration.
HYALURONSYRE
- MANUFACTURING AND USES
Hyaluronsyre findes som nævnt virkelig mange steder – ud over i mennesker, dyr og bakterier findes det også i mange forskelle planter. Særligt høje koncentrationer i menneskekroppen findes i navlestrengen, ledvæske, hud og øjets glaslegeme, men den højeste koncentration blandt alle dyr finder man i hanekamme. I forhold til industriel brug er der overordnet tre fremstillingsmetoder: Ekstraktion fra dyre-væv, bakteriel produktion og in vitro enzym produktion.
For extraction from animal tissue, rooster combs, human umbilical cords, bovine eyes and synovial fluid from cattle have primarily been used. Today, predominantly rooster combs are used for this manufacturing method - and it is widely used - especially for medicinal use of hyaluronic acid. The advantages of this manufacturing method are that it is very well known and the materials to be used are generally quite inexpensive (food production residues), it is naturally produced in the tissue and one can extract hyaluronic acid with relatively high molecular weight and very pure. The disadvantages are that there is a risk of contamination with proteins, nucleic acids and viruses, the yield is not so great, and the purification process must be extensive with the risk of degrading the hyaluronic acid polymers.
Produktion via bakterier startede i 1960’erne – især da man opdagede at hyaluronsyre fra dyrematerialer kan indeholde uønskede proteiner. I dag er det – i forhold til kosmetik – den mest anvendte produktionsmetode. Der findes mange bakterier som producerer hyaluronsyre og udskiller det på ydersiden af cellevæggen, hvorfra det er relativt let at ”høste” det og hvilket i øvrigt gør, at bakterierne er mindre let at opdage for immunsystemet, da hyaluronsyren er helt identisk i mennesker og disse bakterier. De bakterier som primært bruges i dag, er stammer af Streptococcus, desuden bruges også fx Escherichia coli, Lactococcus lactis og Bacillus subtilis. Fordelene ved bakteriel produktion er at teknikken er moden og velkendt, det er relativt let at få et højt udbytte og rimelig høj molekylvægt og meget rent. Man har også mulighed for at påvirker hvor meget hyaluronsyre bakterierne producerer. Ulemperne er, at det kan være GMO-bakterier der bruges og der er en risiko for kontaminering med endotoksiner, proteiner, nukleinsyrer og tungmetaller.
Finally, there is the newest production method: Enzymatic production, in which enzymes from bacteria are used to synthesize hyaluronic acid in vitro. The advantages of this newer versatile method are that it is easier to control the molecular weight, there is no risk of contamination, and the quality can be more easily controlled. The disadvantages are that it is a method that is still under development, it is relatively expensive.
The hyaluronic acid is in some cases modified by inserting crosslinks into the molecule to make it more stable.
By virtue of the many different properties, hyaluronic acid is used for several different purposes, especially in medicine, dietary supplements, and cosmetics. A very important factor for its use is that hyaluronic acid is biocompatible and generally very safe to use on and in humans.
For medical purposes, hyaluronic acid is used for e.g. wound healing in the form of a wound dressing in film form, which can promote wound healing by providing a moist environment in the wound. It is used during eye surgery (e.g. injected into the eye to preserve the shape of the eye) and in eye drops and artificial tears to relieve dry eyes. Another area of medicine where hyaluronic acid is used is in arthritis and osteoarthritis - especially in the knees. Injecting hyaluronic acid solution into the knee joint can reduce pain. There are probably several mechanisms of action behind the analgesic effect. For example, it has been shown that hyaluronic acid can promote the synthesis of components for cartilage matrix, which is characterized by being broken down in osteoarthritis, and inhibit the breakdown of the same and reduce inflammation - in addition to providing a shock-absorbing effect and moisture to the joint. In osteoarthritis, you typically also have less hyaluronic acid in the joint, so injection replaces some of what was lost. However, as described, hyaluronic acid degrades relatively quickly. Hyaluronic acid with crosslinks is more stable and can last a little longer than the all-natural ones. But very interesting the analgesic effect of injecting hyaluronic acid lasts for longer than the hyaluronic acid molecules themselves do in the tissue - perhaps due to a stimulation of hyaluronic acid formation and an anti-inflammatory effect. A few other interesting areas in medicine are that hyaluronic acid can be used to target the medicine to the right place in the body - for example in cancer treatment. And finally, degradation products of hyaluronic acid can be used as a biomarker for certain diseases at an early stage.
In cosmetic surgery, hyaluronic acid is used as a filler, where hyaluronic acid (possibly stabilized with crosslinks or otherwise) is injected into the skin to give fullness and smooth out wrinkles. The effect typically lasts around ½-1½ years, and it is generally a very safe treatment. The most common side effects are pain, redness and itching.
Hyaluronic acid is also used in supplements where it has shown some but not very strong evidence for effect against osteoarthritis. However, it is shown that orally ingested hyaluronic acid is absorbed and distributed in the body.
In cosmetics, hyaluronic acid is a rather desired component - especially due to its moisturizing properties. Moisture is a very basic component of the skin and often part of a solution to maintain a nice and functional skin - and to relieve more skin problems. As with the other target areas, the molecular size of hyaluronic acid is important for its properties relative to skin. In general, hyaluronic acid with a high molecular weight will not enter the skin but provide a protective film over the skin - and thereby provide moisture. Hyaluronic acid with a low molecular weight will more easily be able to get a little into the skin and bind moisture there. Many studies have been done with hyaluronic acid in cosmetics. One study, for example, has shown that 0.1% low molecular weight hyaluronic acid (50-130 kDa) was better at reducing wrinkles around the eyes and improving the moisture level and elasticity of the skin, while higher molecular weight hyaluronic acid generally also has positive effects in slightly less degree.
The concentration of hyaluronic acid in cosmetics is usually below 1%. In addition to its effect on the skin, it also has a thickening and moisturizing property in the product itself. It is most often Sodium Hyaluronate, which is used in cosmetics.
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Wikipedia webside. Hyaluronic acid. Lokaliseret 29. Januar 2022: https://en.wikipedia.org/wiki/Hyaluronic_acid
Wikipedia webside. Wound healing. Lokaliseret 31. Januar 2022: https://en.wikipedia.org/wiki/Wound_healing
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