Comparison of noncross-linked and cross-linked hyaluronic acid with regard to efficacy of the proliferative activity of cutaneous fibroblasts and keratinocytes in vitro

J Cosmet Dermatol. 2013 Mar;12(1):36-40. doi: 10.1111/jocd.12024.


Background: Intradermal application of hyaluronic acid (HA) in varying chain length and cross-linking density is used routinely for hydrodynamic volume replacement of the extracellular matrix to reduce the clinical effects of aging.

Objectives: In vitro data show that via receptors of the hyaladherin group hyaluronic acid has additionally direct or indirect effects on cells. In the case of native noncross-linked HA, it has been proved that the proliferative and metabolic activity of cutaneous fibroblasts can be increased. The aim of this study was to investigate whether these effects can be proved also for cross-linked HA and how these effects can be quantified for different preparations.

Materials and methods: The effect on proliferative activity in cultures of native cutaneous fibroblasts and keratinocytes was investigated for noncross-linked HA, for noncross-linked HA with added glycerol, for HA that was stabilized in the carboxyl and hydroxyl groups per inner esterification, and for HA that was chemically cross-linked by 1,4-butanediol-diglycidylether, mixed in small particles in a biphasic compound with native HA, each in different concentrations (0.1, 1.0 and 10.0 mg/mL).

Results: HA that was stabilized in the carboxyl and hydroxyl groups per inner esterification induces the strongest proliferative effect on both cell types. Native noncross-linked HA and chemically cross-linked HA show a rather modest proliferative effect and on fibroblasts only, whereas noncross-linked HA with added glycerol in high concentrations provokes a rather antiproliferative effect.

Conclusions: The data show that HA does induce direct effects on cells depending on type and density of the cross-linkage. The practical relevance in terms of a metabolic filler effect needs to be verified in clinical studies.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / pharmacology*
  • Cross-Linking Reagents*
  • Extracellular Matrix / metabolism
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Humans
  • Hyaluronic Acid / pharmacology*
  • In Vitro Techniques
  • Keratinocytes / drug effects*
  • Keratinocytes / metabolism


  • Adjuvants, Immunologic
  • Cross-Linking Reagents
  • Hyaluronic Acid