Skin aging is a universal and inevitable process that is characterized
by alterations in keratinocytes activities, epidermal function, and dermal changes. Epidermal senescence is characterized
by barrier impairment, xerosis, slower cell turnover, and atrophy. In the epidermis, ECM components form an integral
part of the hemidesmosomes and mediate keratinocyte attachment to the underlying base membrane. Extracellular HA is the major GAG in the epidermal and dermal ECM of most mammalian tissues. Epidermal HA levels are tightly correlated to keratinocytes proliferation, maturation, and differentiation. Elevated levels of HA in the epidermis are linked to highly proliferative keratinocytes. Epidermal HA is localized mainly between cells in the basal layers, disappearing during keratinocytes
differentiation and becoming undetectable at the granular layer of the stratum corneous. The relationship between elevated
HA levels and actively proliferative keratinocytes is also seen in pathological conditions such as epidermal hyperplasia and psoriasis.64,70
Interestingly, histological findings show the presence of intracellular
HA in these highly proliferative cells, which disappears as keratinocytes are differentiating. The presence of extracellular HA in the upper layers of the epidermis is thought to maintain diffusion and to open up spaces to facilitate cell migration. Epidermal
HA distribution is characterized by compact pericellular coats that are primarily maintained by the presence of CD44.64,71 HA concentrations in these pericellular areas reach levels as high as 2.5 mg/mL.70,72,73 Epidermal HA is more stable (less susceptible to degradation) than dermal HA, probably due to its association with hyaladherin (HA-binding proteins) that protects it against internalization and the action of HYALs.74,75
HA content of the dermis is significantly higher than in the epidermis, with highest levels in the papillary dermis. Dermal HA is in continuity with the lymphatic and vascular systems, regulating water balance, osmotic pressure, and ion flow, and functioning as a sieve, excluding certain molecules, enhancing the extracellular domains of the cell surfaces and stabilizing skin structures by electrostatic interactions. The main producers
of HA in the dermis are papillary dermal fibroblasts. Dermal HA has access to the lymphatic system and is thought to play a role in regulating water contain in the dermis.10
TOPICAL HYALURONIC ACID: TRUTHS AND HOPES
Skin hydration is highly correlated with the content and distribution
of dermal GAGs, more specifically HA. One of the changes linked to photo-aged skin is a reduced level of HA and elevated levels of non-water binding chondroitin sulphate proteoglycans, resulting in a paradoxical increase in GAGs with decreased hydration.76 In addition, the presence of solar elastosis in photo-aged skin further aggravates the decreased water binding capacity by displacing normal ECM structures with abnormally deposited elastotic material.77 A higher level of fragmentation and aberrant deposition of HA is also linked to aged skin, diminishing even further the net decrease in this water trapping capacity.
One commonly used approach in the cosmetic industry is to improve water retention or to decelerate water loss with the use of moisturizers, which attempt to increase cutaneous water levels by using occlusive ingredients such as cocoa butter, lanolin, shea butter, and mineral oil. While these ingredients
provide a smooth-feeling skin, only a temporary filling of the spaces between desquamating skin scales is accomplished. Due to the role of high MW HA in water retention,
a logical step is to develop topical HA products that restore the natural hydration of dried or aged skin. Nonetheless,
there are 2 major obstacles that prevent this logical solution from being the expected “holy grail†of skin hydration:
total lack of penetration and rapid degradation of externally applied HA. In addition, the reduced capacity of aged epidermis to bind HA (due to decreased levels of CD44) further prevents topical HA from reaching the epidermis and restoring endogenous levels of this GAG.78-81 In recent years, encapsulation and other targeted versions of HA-delivery have been attempted, but have proven to be unsuccessful in restoring epidermal HA levels.
HA
Skin aging is linked to a decrease in the levels of HA in both dermis and epidermis. Restoration of lost dermal HA is successfully
accomplished by injectable dermal fillers, which due to chemical modifications such as cross-linking are able to provide
a long-lasting space-filling. However, as discussed in the previous section, topically applied HA preparations are unable
