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To understand the working of hyaluronic acid, it is essential to firstly have an idea of what makes up the skin and to have an understanding of the functions of the skin.
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The skin is the organ that is the body’s shield against the external environment. It is made up of two parts, on the outside is the epidermis, which is a tissue consisting of many layers of cells with almost no other substance between them. These cells are known as epithelial cells. Lying directly underneath the epidermis is the dermis, a tissue that contains nerve endings, sweat glands, sebaceous glands and blood and lymph vessels.
The epithelial cells in the epidermis come in many different forms and structures and have various names. One of these groups or strata of cells are known as keratinocytes. The layer of keratinocytes at the bottom of the epidermis form a strata of cells known as the basal cell layer and the keratinocytes are known as basal keratinocytes.
The basal keratinocytes lie on a basal lamina, which is not made of cells but contains different types of collagens, proteoglycans and multi-adhesive glycoproteins. This basal lamina is the seam between the epidermis and the dermis.
Basal keratinocytes continually split and form new cells, which move up towards the spinous (spiny or spiky) cell layer that covers the layers of basal keratinocytes. These keratinocytes in the spinous cell layer in their turn divide and the daughter cells move up towards another layer of cells in the epidermis, called the granular cell layer, and then again from the granular cell layer to the surface layer of the epidermis, called the outer cornified layer or the stratum corneum.
The basal cells, spinous cells and granular cells are living cells, while the cells in the cornified layer, known as corneocytes, are not.
This process of cell movement upward from the basal layer, though the spinous and granular layer, towards the cornified layer is a synchronized ongoing process. This process is supported by a large network of keratin filaments between the junctions of the cells (known as demosomes) and attachments between the basal cells and in the basal cell lamina (known as hemidemosomes).
Hyaluronic acid is a glycosaminoglycan that is found in most body tissue, as a part of the extracellular matrix, or fluid surrounding the cells. It is needed by the body to promote the creation of new cells, the movement of cells and is an essential component in cell surface receptor interactions.
Hyaluronic acid was known as a “goo” molecule until the late ‘70’s and is part of synovial fluid found in between the joints. This fluid lubricates the joints and reduces friction.
Hyaluronic acid was identified about 50 years ago as a major component of the skin and was thought to originate solely in the dermis until a few years ago. This belief was held due to the fact that the dermis is the major part of the skin and the role that hyaluronic acid played in forming matrices in connective tissue was known.
It was also hard to isolate hyaluronic acid in the epidermis, as the fluid surrounding the keratinocytes in the epidermis is minimal and tests did not pick up any sign in the epidermis. However, current research into the microscopic structure of the epidermis has shown signs of hyaluronic acid surrounding the keratinocytes in the epidermis.
It is well known that hyaluronic acid is a space filler and is used by the body to organize the intracellular substance of a tissue, but it is less clear as to what hyaluronic acid does in epithelial tissue (such as the epidermis), as the cells are closely packed and there does not seem to be space for much fluid.
One would think that too much hyaluronic acid in this tissue would negatively affect the cohesion between the epithelial cells and the permeability of the epithelial barriers. Indeed, it is found that the tissue of the walls of the intestines, lungs and most of the reproductive organs hardly express any hyaluronic acid.
However, recent laboratory research shows that parts of the skin, throat and vaginal mucous membranes have large concentrations of the acid. Tests show that the concentration of the acid could be as high as 2.5 mg/ml, which is surprising, considering the restriction to the small extra-cellular space in this epithelial tissue.
Research using organ cultures of the skin show that hyaluronic acid is actively metabolized in the skin and is not simply a space filler. Human skin explants showed a half-life of about 1 day for dermal as well as epidermal hyaluronic acid.
The epidermis is sealed off, containing no blood vessels and only molecules that are small enough to infiltrate the basal lamina underneath the basal keratinocytes can enter. The outer stratum corneum of the skin forms a tighter seal as the corneocytes are terminally differentiated to prevent even water from entering.
The lower basal boundary and the upper corneal boundary confine the metabolism of the high molecular weight hyaluronic acid to the keratinocytes within the skin. Studies show that free radicals mediate the breakdown of hyaluronic acid by keratinocytes, since free radical scavengers, such as superoxide dismutase, slow down the breakdown of hyaluronic acid when added to human skin cultures.
Although no specific data is available to determine the exact details of how hyaluronic acid is broken down in the skin, tests show that hyaluronic acid produced by the body binds to the surface of keratinocytes (or skin cells), most probably in lysosomes.
The structure, thickness and turnover of skin cells vary according to the development and physiological state of the skin. Hyaluronic acid is vital to the growth in skin cells, the movement of skin cells (keratinocytes) and the changes in skin cells, during the progression of the cells through the skin. Hormones, cytokines and growth factors control the metabolism of hyaluronic acid.
Retinoic acid reduces the number of junctions or demosomes that attach keratinocytes and reduces the synthesis of keratins that are associated with the growth and death of outer keratinocytes. This prevents the formation of a structurally and functionally normal outer skin layer or stratum corneum. Retinoic acid also causes the body to produce more hyaluronic acid and studies show that it doubles the content of hyaluronic acid in the epidermis in human skin organ culture.
Retinoic acid causes the space between the cells to fill with hyaluronic acid, which perhaps causes a reduced number of demosomes and prevents keratinocytes to adhere tightly, as they do not have a proper junction that attaches the one to the other. This prevents proper terminal differentiation (the process in which cells lose their nuclei but remain functional).
Cortisol or Hydrocortisone is popular as an anti-inflammatory and to inhibit cell growth. It prevents the catabolism of hyaluronic acid at all doses and stops the production of hyaluronic acid at large doses. Cortisol therefore stabilizes hyaluronic acid at all doses and reduces the content of hyaluronic acid in large doses, augmenting normal differentiation.
The fact that retinoic acid increases hyaluronic acid production and hydrocortisone inhibits hyaluronic acid production, logically leads one to assume that hyaluronic acid is an essential requirement for terminal differentiation.
Epidermal growth factor (EGF) and transforming growth factor alpha (TGF – alpha) encourage wounds to heal faster and stimulate the skin by stimulating keratinocytes movement and production. Hyaluronic acid is also well known for stimulating movement of the keratinocytes.
This similarity should be noted in conjunction with the above-mentioned retinoic acid and cortisol treatments. This action further strengthens the idea that enhancing hyaluronic acid production is associated with delayed cornification of keratinocytes (thickening the skin), whereas terminal differentiation is a result of reduced production or clearance of hyaluronic acid.
A high presence of hyaluronic acid is found in most fetal tissue, forming a gooey, highly hydrated intracellular substance in which embryonic cells have the space to develop and multiply rapidly.
Hyaluronic acid is found in a high concentration in the intracellular fluid and space surrounding mesodermal cells, as well as in the outermost part of 3 germ layers (the ectoderm). This high concentration decreases during growth, formation and change in the tissue.
During this process of change, formation and growth, hyaluronic acid interacts in intensely different ways with the receptors of the cells and with the molecules in the fluid and space surrounding the cells.
A receptor called CD44, which is a hyaluronan (hyaluronic acid) receptor, is very important in the process of epidermal differentiation (The process by which cells or tissues undergo a change toward a more specialized form or function). Various types of CD44 are found in copious amounts on keratinocytes in the epidermis.
When still in the womb and developing, the human skin is covered by two layers of cells, the first called the epithelium, which lie above the developing mesoderm, and the second, the outermost layer of the epidermis or the periderm. Both of these layers contain hyaluronic acid on their surfaces, but do not contain CD44 receptors. The CD44 receptors only appear when stratification genes are activated and the first layer of cells start appearing above the basal cell layer (an intermediate cell layer). This compares with studies done in adult skin, where CD44 and hyaluronic acid are abundant in stratified and not simple epithelia (the covering of most external and internal organs of the body).
This leads one to believe that finding CD44 receptors is indicative of epidermal growth and in normal change towards a more specialized form or function in cells and tissue. It is interesting to note that in squamous cell carcinomas a down-regulation of CD44 is found and a loss of hyaluronic acid from cell surfaces.
The hair follicles, sebaceous glands and sweat glands start developing in sequence out of the fetal epithelium or covering tissue. The first sign of development of ectodermal parts (hair follicles etc) is the formation of a tightly packed collection of epithelial cells, which causes the loss of hyaluronan (hyaluronic acid) and CD44. The same reaction occurs when limbs start to form i.e. loss of hyaluronan and CD44. In other words, when tight cell collections occur, there is a loss of epithelial hyaluronic acid and its receptor, CD44.
Hyaluronic acid is used to maintain the space between the lower cells in the layers of cells in the epidermis and to help the movement of food to and waste products from the upper cells. When concentrations of hyaluronic acid is high in basal layer, it causes the layer to swell, which may upset the balance of demosomes and the adherence of adjacent cells and cause them to be replaced faster. This means that hyaluronic acid may cause constant cellular change during the lifecycle of a keratinocyte, as it forms out of the division of a columnar basal cell until it ends up as a flat corneocyte in the stratus corneum of the epidermis.
During the process of cell division, new cells are either retained in the basal layer, or move upward, undergoing terminal differentiation until they reach the stratum corneum, where they become cornified dead cells. The time it takes for cells to become cornified depends on the thickness of the epidermis. Current research suggests that if a cell is connected to the intracellular space through specific cell surface receptors it delays cornification and aids the survival of the cell and promotes connective tissue cell re-growth.
Epidermal keratinocytes in the basal layers do have hyaluronan as the main component in the extra-cellular fluid. Current research indicates that it is a survival signal when hyaluronan interacts with surface cell receptors and that this indicates a delay in terminal differentiation.
Hyaluronic acid is shown to be an effective scavenger of free radicals and may also be effective when scavenging oxidants caused by ultraviolet radiation. The extremely fast turnover may help eradicate and remove harmful substances from the epidermis. Immune system cells, such as Langerhans cells and lymphocytes move through the epidermis. Hyaluronic acid creates space for these cells and also provides a degree of receptiveness in the epidermis for their CD44 receptors.
Studying the keratinocyte cell line, using newborn rat epidermis, it was found that hyaluronic acid is present in very high concentrations in extracellular space between the layers of keratinocytes in the rat epidermis and had a turnover period of less than one day. This suggested that hyaluronic acid is a space filler that is part of the process of differentiation in keratinocytes, helping in their upward migration and shape change when they differentiate. The study also showed that hyaluronic acid provided extracellular space for the exchange of nutritional and regulatory metabolites for the upper spinous cells, and that it encouraged keratinocyte motility and survival.
Hyaluronic acid is currently used in a number of clinical applications such as; the supplementation of joint fluid in arthritis; as a surgical aid in eye surgery and to encourage healing and regeneration of surgical wounds.
It is also the main ingredient of many cosmetic fillers, which are injected into the surface skin to reduce tissue defects in soft skin, such as Restylane (trade name) and is one of the ingredients for a topical treatment for actinic keratoses, which was approved for use in the USA.
This treatment is said to be very effective and a much safer alternative to the regular treatment foractinic keratoses, which is cryoblation, curettage or dermabrasion.
Hyaluronic acid has recently become popular as an ingredient for topical applications in skin care. Although hyaluronic acid is widely used in fillers, it has only lately been discovered that hyaluronan (hyaluronic acid) freely penetrates the skin and may be used as a vehicle to carry other ingredients deep into the dermis, the bottom layer of the skin. REF 335
Aging causes our bodies to loose more and more hyaluronic acid, which causes a drop in the moisture levels in our skin, covering membranes of our internal organs and joints. After the age of 40 the process becomes more visible and our skin starts to loose its elasticity, with lines and wrinkles forming.
Hyaluronic acid in the correct quantities causes a rise in the extra cellular fluid in-between the cells, creating a smoother, moisturized skin, by binding with the same amount of water molecules.
Desquamation is a process whereby skin cells transverse in a sequential manner from the basal (lowest) layer in the dermis up and outwards toward the stratus corneum, where the dead cells flake off. This process is sometimes thrown out of sync by various external factors such as pollutants, age, and environmental conditions.
A corneocyte is a skin cell that has reached the external layer of the skin, the stratus corneum. Hyaluronic acid improves the cohesion of corneocytes, in other words it prevents dry and flaky skin.
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