By John Jesitus
August 1, 2007, Dermatology Times
Irvine, Calif. To understand the injection characteristics of a hyaluronic acid (HA)-based dermal filler and how the material performs clinically, one must understand how it was made, an expert says.
“Multiple factors affect injectability or extrusion force. The two most important ones are known as G â€” the elastic modulus, which refers to how hard a product is and viscosity,” says Ahmet Tezel, Ph.D., director of research and development, Allergan Medical, Irvine, Calif.
To help dermatologists understand the concept of gel hardness, Dr. Tezel explains that if one sandwiches an HA gel between two plates, the higher the gel’s G value, the more force it will take to push the top plate a small distance horizontally while holding the bottom one stationary. More specifically, he says G denotes the ratio of shear stress (force per unit area of the plate) to the shear strain imposed (the ratio of the horizontal displacement to the vertical distance between plates).
When manufacturers design HA fillers, he says, “One of the limitations they face is injectability, because HA dermal fillers are very viscous materials.”
Part of the solution to this problem involves incorporating some unmodified or uncross-linked HA, which flows much more easily than HA with molecules that are cross-linked, Dr. Tezel tells Dermatology Times.
However, he says, “The downside of using uncross-linked HA is that it doesn’t provide persistence and is rapidly broken down in the skin. So in the ideal filler, one wants minimal amounts of uncross-linked HA.”
Cross-linking refers to the process by which U.S. manufacturers bind HA polymer chains to each other, currently by using either 1,4-butanediol diglycidal ether (BDDE) or di-vinyl sulfone (DVS), Dr. Tezel explains.
Both react with hydroxyl sites on HA chains, thereby slowing down enzymatic, mechanical and free radical degradation of dermal fillers after they’re injected into the skin, he adds.
“Besides adding uncross-linked HA,” Dr. Tezel says, “another point of differentiation between manufacturers is how they size down the gel mass” that results from linking HA polymer chains together. If they don’t do this, he notes, “It will just clog the needle.”
One approach to breaking down HA gel mass involves pushing it through sieves or screens.
The screens have openings of a certain size and shape that create particles of roughly corresponding size and shape, Dr. Tezel says. “That specifically sized particle creates a gel with a granular consistency.”
In contrast, he says Allergan does not use screens to specifically size its HA gel. Rather, Dr. Tezel says, “We create random sizes and shapes” through a proprietary homogenization process.
“By creating random sizes and shapes,” he explains, “we create a uniform consistency or a smooth-looking gel. The only HA product in the United States that uses this type of formulation is Juvéderm® Injectable Gel .”
If one looks at this product under a microscope, Dr. Tezel says, “One will not see it as a granular particle product. One will see a very smooth formulation.”
Manufacturing processes affect not only how an HA filler extrudes, but may also affect how the product feels to the patient inside his or her skin, Dr. Tezel says.
Products manufactured by sieving techniques have a narrow distribution of gel particle sizes and usually a higher viscosity unless they include additional uncross-linked HA, he says. However, Dr. Tezel adds, “The uncross-linked HA will be quickly metabolized and won’t contribute to long-term clinical outcome.”
Conversely, he explains, fillers that use advanced sizing techniques to achieve a broad distribution of particle sizes and a smooth consistency offer the advantage that they require less uncross-linked HA to achieve even injection characteristics.
“Along with smooth injections,” he says, “such products’ higher percentage of cross-linked HA may improve persistence and clinical outcome.”
Dermatologists have long wondered why some dermal fillers inject more smoothly than do others, but until recently, very little information in this regard was available, he adds.
However, Dr. Tezel says, “One of the things Allergan wants to do is to raise the scientific level in dermal fillers.”
Therefore, he says that in the future, “We’re going to publish a lot of literature.”
Disclosure: This research was supported by Allergan Medical.