Reviving the Skin From Within: Mechanistic Insights Into a Well‐Tolerated Dermal Filler—
CPM
‐
HA20G
Kay Marquardt, Christian Hartmann, Sonja Sattler, Je‐Young Park, Ting Song Lim, Luis Alberto Parra Hernandez, Christina Wollenburg, Daniela Schäfer, Sarah Hetier‐Jaccoud, Thomas Hengl ABSTRACT
Background
Dermal fillers composed of hyaluronic acid (HA) combined with glycerol have been clinically shown to enhance skin hydration and quality; the precise mechanisms underlying their efficacy have yet to be fully elucidated.
Aims
Investigation of the dual hydration mechanisms, cell protection and tolerability, and tissue compatibility of the cohesive polydensified matrix (CPM) filler containing HA and glycerol (CPM‐HA20G), focusing on glycerol's unique role.
Methods
Primary normal human epidermal keratinocytes, in vitro skin, ex vivo human skin models, and an in vivo study were used to evaluate CPM‐HA20G, with additional assessments of its humectant, glycerol. Comparisons were further made with a cross‐linked HA filler containing sorbitol (HA12.5S) indented for similar use, as well as with the humectants sorbitol and mannitol. Gene expression analysis, protein analysis, cell‐based assays, 3D micro‐computed tomography (μCT), TEWL, corneometry, and histology were performed to assess aquaporin‐3 (AQP3) modulation, cellular stress levels, protection from UVB—or H 2 O 2 ‐induced oxidative stress, hydration dynamics, tissue integration, and inflammation.
Results
CPM‐HA20G immediately increased hydrated tissue volumes by 40% within 10 min and 63% after 120 min post‐injection, as measured via μCT indicating improved inner tissue hydration. Progressively, CPM‐HA20G increased surface hydration values from the inside out, whereas the glycerol component of CPM‐HA20G contributing a pronounced hydration effect. Glycerol uptake in keratinocytes occurred without upregulating AQP3 expression, in contrast to sorbitol and mannitol, which triggered AQP3 overexpression ( p < 0.001), along with the cellular stress marker, phosphorylation of P38 (pP38) ( p < 0.0001) and reduced keratinocyte viability ( p < 0.001, p < 0.01). Similarly, AQP inhibition by DFP00173 or phloretin elicited a comparable P38 stress response, which was attenuated by glycerol treatment. Compared to sorbitol and mannitol, glycerol demonstrated well cellular tolerability. Glycerol treatment reduced UVB—or H 2 O 2 ‐induced reactive oxygen species (ROS) in keratinocytes by 68% ( p < 0.0001), highlighting its antioxidative capacity. Furthermore, histological analysis verified improved tissue integration and reduced inflammatory response for CPM‐HA20G relative to the HA‐filler HA12.5S containing sorbitol.
Conclusions
This preclinical study demonstrates that CPM‐HA20G achieves rapid tissue hydration via a dual hydration mechanism and is well tolerable with favorable tissue integration. Glycerol was found to play a unique role in enhancing hydration without inducing stress responses, providing antioxidative capacity and cell protection. These findings provide a mechanistic basis for the clinical efficacy of CPM‐HA20G.