Chapter 3 Biophysical Properties of Hyaluronic Acid
Introduction
Hyaluronic acid (HA) is a glycosaminoglycan composed of multiple repeating units of D-glucuronic acid andN-acetyl-D-glucosamine (Fig. 3.1). It occurs naturally in several tissues in the human body, including the skin, synovial fluid of the joints, vitreous humor in the eyes, and cartilages. Approximately 50% of the total body HA is found in the skin. At physiologic pH, it is a highly charged polyanionic polymer which binds water extensively, retaining water that is up to 1,000 times its volume. 1
The first study with filler injections dates back to 1893, when Neuber used autologous fat to fill a facial defect. The 1980s saw the arrival of filler agents derived from animal collagen (Zyplast and Zyderm; Allergan, previously Inamed); in March 2003, human collagen derivatives, such as Cosmoderm, Cosmoplast, and Evolence, were marketed; and in December 2003, non-animal-derived stabilized HA (NASHA) (Restylane, Q-Med, Uppsala, Sweden) was introduced. Other brands of HA have been marketed since then that were produced by biofermentation ofStreptococcus sp; these represent a large step forward, as they have the advantage of greater durability, can be used immediately without the need for prior allergy testing, and have a predictable capacity of volume replacement. 2
Physical and Chemical Characteristics
The combination of different physical and chemical properties determines the final characteristics of the product.
Molecular Weight and Concentration
The molecular weight (MW) of HA is proportional to the number of repeating disaccharides composed of D-glucuronic acid andN-acetyl-D-glucosamine. The MW of HAs used in the manufacture of fillers varies from 500 to 6,000 kDa.
The concentration corresponds to the total HA expressed in mg/ml. The total concentration of HA consists of insoluble HA gel and soluble free HA. Some products provide free HA as a soluble fluid component to the gel in order to facilitate extrusion of the filler through finer needles. Despite the fact that not all manufacturers add HA fluid to their fillers, a fluid component is always present, usually generated during the manufacturing process. These soluble fluids are easily metabolized and do not contribute toward the durability and efficacy of the product. Only crosslinked HA resists enzyme degradation and degradation by free radicals. 1
Crosslinking
In its natural form, HA has a half-life of 1 to 2 days. It is degraded by the hyaluronidase enzyme and by free radicals, and is metabolized by the liver into water and carbonic gas. Crosslinking is an important process for increasing duration, and also because it can affect the biomechanical characteristics of the filler. The most common crosslinkers are divinyl sulfone, 1.4-butanediol diglycidyl ether (BDDE), and di-epoxides. In crosslinking, the crosslinker forms a bond between two strands of HA (Fig. 3.2). In the case of pendant HA, the crosslinker only forms a bond to one HA strand forming a pendant group. An increase in crosslink density reduces the distance between crosslinked segments, so that when a load is applied, greater force is required for extrusion. Therefore, increasing crosslink density increases the hardness or stiffness of the gel. When a more flexible gel is required, the degree of crosslinking should be decreased and the degree of pendant HA increased.
Manufacturing of non-animal-derived stabilized HAs (Restylane) and Hyalcross products (Juvedérm) starts with crosslinking smaller portions (approximately 200 to 300 kDa), while manufacturing of HAs with a polydensified cohesive matrix starts with crosslinking larger portions (approximately 800 kDa). Moreover, the latter presents nonuniform crosslinking, which is reached after a second stage of crosslinking and the addition of more HA. This results in two patterns of density in the product, despite its still being monophasic. The areas with the greatest crosslinking are firmer and confer duration to the product, while those areas with less crosslinking make the product more malleable. 1
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