The HA-collagen connection

Key Points

ANN ARBOR, MICH. — Results of a study conducted by researchers at the University of Michigan department of dermatology provide interesting new insight into the underlying mechanism for improved skin appearance following injection of the dermal filler nonanimal stabilized hyaluronic acid (NASHA; Restylane, Medicis Aesthetics).

In an article published in the February issue of Archives of Dermatology, John J. Voorhees, M.D., and colleagues reported injection of the filler into photodamaged forearm skin resulted in de novo collagen synthesis. In an initial pilot study they observed new collagen production within one week after the filler injection, and their assessments showed collagen biosynthesis was still ongoing when the last biopsy was taken 13 weeks post-treatment.

Investigations performed to determine the underlying pathway for fibroblast activation suggested a primary role for filler-induced mechanical stretching of the collagen-producing cell. That mechanism would account as well for the observed increases in expression of pro-fibrotic growth hormones and tissue inhibitors of matrix metalloproteinases (TIMPs). "It's commonly believed that the cosmetic benefit of cross-linked hyaluronic acid fillers represents a volume effect, which is secondary to the physical presence of the material and its ability to absorb water. However, we surmised that dermal injection of NASHA into photoaged skin might induce biochemical changes through restretching of collapsed fibroblasts. In fact, we found that the dermal filler injection caused the fibroblasts to assume the biosynthetic phenotype that is characteristic of these cells in young and photoprotected skin and thereby helps to restore skin structure," explains Dr. Voorhees, chair and Duncan O. and Ella M. Poth Distinguished Professor of Dermatology, University of Michigan, Ann Arbor.

WAKE-UP CALL "Prior to this study, we thought that photodamaged fibroblasts were permanently altered and could not be rejuvenated," Dr. Voorhees notes. "That may still be true to some extent, but at least in the context of collagen synthesis, our findings indicate that function can be reawakened."

The study involved 11 healthy, older subjects (mean age, 74 years) with mild-moderate or moderate photodamage of their forearm skin. Each participant received three injections with the filler into separate sites on one forearm and three injections with vehicle (normal saline) into the contralateral forearm. Biopsies were obtained at the injection sites after four and 13 weeks and evaluated for the presence of NASHA with immunohistochemical staining, and for collagen synthesis using immunohistochemical analysis, quantitative polymerase chain reaction, and electron microscopy. The results showed the presence of filler material in the middle and lower dermis at both four and 13 weeks, although the amount of residual filler decreased over time while collagen accumulated.

A variety of investigations were performed to examine the mechanisms whereby the filler injection induced collagen synthesis. Those studies showed the dermal filler injection was associated with increased expression of genes for connective tissue growth factor, transforming growth factor-betas 1, 2 and 3, and TIMP 1, 2 and 3. There were no significant changes in gene expression of matrix metalloproteinases (MMPs) investigated.

"The activity of the NASHA injection to increase TIMP expression is a positive finding because it assures that the new collagen formed will stay and not be degraded by MMPs that are upregulated in photodamaged skin," Dr. Voorhees notes.

COSMETIC TRANSLATION Whether a single injection of NASHA results in enough collagen production to have a clinically visible effect is not known. However, Dr. Voorhees believes that multiple injections would result in sufficient collagen accumulation to make an impact on skin appearance.

"While previous studies show that injected NASHA disappears within 6 to 9 months, collagen has an estimated half-life of 15 years. Therefore, while the cosmetic effect from the volume-occupying properties of the filler dissipates over time, the benefit of new collagen production is long-lasting. If enough collagen is produced, there will be cosmetic benefits with smoothing of the skin. Considering the potential for a cumulative effect and its durability, there are also implications for using lesser volumes of the filler per injection, which would reduce the treatment cost," observes Dr. Voorhees.

MORE TO THE MOA The University of Michigan researchers are continuing their investigations at the basic science level to elucidate the signaling pathways activated by the dermal filler injection with the idea that information could lead to the development of topical modalities able to act via the same mechanisms.

They also note that while NASHA injection into facial skin likely induces the same biological response as was observed in the forearms, it cannot be assumed that other dermal fillers act similarly to stimulate collagen production.

"There may be more to the mechanism of action of NASHA-induction of increased collagen production than simple cell stretching, and differences in biophysical properties between fillers may cause them to interact differently with the fibroblasts," Dr. Voorhees explains.

"Determining the potential for the various fillers to induce collagen synthesis would require each to be studied individually."

Disclosures
The researchers received donated product from Medicis Aesthetics for their study, but that company was not involved in the study design, conduct, analysis or reporting. Medicis also did not see the study manuscript until it was published. Dr. Voorhees has no financial interest in Medicis.

Reference
Wang F, Garza LA, Kang S, et al. Arch Dermatol. 2007;143:155-163.

For more information
John J. Voorhees, M.D.
[email protected]