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 limitations

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 influences

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.