In photoaging and intrinsic aging, says Dana L. Sachs, M.D., "Whether the culprit is UV light or time, we see a vicious cycle of collagen fragmentation driven by ROS (reactive oxygen species). We know this because the addition of certain antioxidants will basically turn this cycle off. But it's more complicated than that. It's very difficult to determine optimal doses, delivery and timing." Whatever intervention one uses, it's impossible to halt the process completely, says Dr. Sachs, associate professor, department of dermatology, University of Michigan, Ann Arbor.
Soft-tissue fillers represent one option for intervening in the above processes. Although fillers clearly improve the appearance of aged skin, "We wonder from a scientific perspective whether the filler's addition of volume alone explains the improvement, or are there other mechanisms driving this?" Dr. Sachs says.
To address this question, researchers at the University of Michigan examined the impact of cross-linked hyaluronic acid (HA/Restylane, Medicis Aesthetics) versus saline injected into photoaged forearm skin. Using biopsy samples taken at weeks four and 13 post-treatment, Dr. Sachs says, "Assays were performed to look for evidence of new collagen production."STUDY RESULTS In immunohistologic analysis, week-four samples from sites that had received cross-linked HA showed that elongated fibroblasts had filled in the gaps where HA had been injected, Dr. Sachs says. In contrast, saline-treated sites contained many fibroblasts left in a collapsed, shriveled state by the aging process (Wang F, Garza LA, Kang S, et al. Arch Dermatol. 2007;143(2):155-163).
Under electron microscopy, "In the saline-injected sites, the rough endoplasmic reticulum was not that busy" making new collagen, she says. But in cross-linked HA sites, "We saw abundant endoplasmic reticulum," which meant that the body's collagen-production machinery was humming.
Similarly, Dr. Sachs says that cross-linked HA-injected sites showed significant increases in expression of procollagen I at four and 13 weeks post-treatment. "Direct measurements of procollagen I protein showed a 90-fold increase in cross-linked HA-treated sites," she says. "We also found that cross-linked HA induces connective tissue growth factor (CTGF) gene expression."
MECHANISM OF ACTION ROS block the transforming growth factor (TGF)-beta pathway, which is the major pathway for new collagen formation. "We were able to show with cross-linked HA that the injection significantly increased all three isoforms of TGF-beta, leading to an increase in collagen production," Dr. Sachs says.
Mechanistically, "Cross-linked HA stretches relaxed fibroblasts, creating an increase in mechanical tension," she says. "The stretching causes fibroblasts to form new collagen, and stretching increases TGF-beta and CTGF, which are profibrotic, collagen-producing pathways. Stretching also increases tissue inhibitors of matrix metalloproteinases (TIMPs), which prevent collagenase from degrading new and mature collagen."
Along with the space-filling function of cross-linked HA, "We know that there's also water binding, because HA draws in water. But we've also demonstrated that there is new collagen production, as well as preservation of mature collagen," Dr. Sachs says.
Other tools for impacting the aging process at the molecular level include sunscreens, which block UV and ultimately the formation of ROS, Dr. Sachs says. "Retinoic acid and retinol also impact these pathways, specifically through TGF-beta," she says.
LONGEVITY OF RESULTS As for practical considerations, Dr. Sachs says collagen has a 15-year half-life. Therefore, if cross-linked HA injections stimulate collagen production and patients undergo repeated injections, "They can expect longevity from their results.
"Repeated cross-linked HA injections would be expected to produce a durable accumulation of collagen, and many patients who undergo filler injections actually see this," she says. "Patients who come in regularly tend to need less product, and they get longer-lasting results from the product that has been injected."
In an unpublished study, the University of Michigan team examined the impact of cross-linked HA on naturally aged skin, specifically of the buttocks. "What we found was very similar to what we've seen in photoaged skin," Dr. Sachs says. This includes induction of type I procollagen mRNA and type I procollagen protein, plus epidermal thickening.
Disclosures: The research presented by Dr. Sachs was funded by the University of Michigan.