croneedling. Increased volume (red) correlates with swelling on the comparator side versus the test product (Figure 7).
Additional Benefits Related to Active Ingredients in Topical Product: Volumetric Enhancement and Regeneration
Elastin (and collagen) stimulation synergy with fillers (Figure 8 and Figure 9)
Elastin is an assembly of microfibrils and tropoelastin (or soluble elastin). Elastin fibers are formed first by the synthesis of fibrillin microfibers that intertwine and then associate with tropoelastin (TE) protein molecules. TE molecules are bound together and cross-linked together with fibrillin fibers by lysyl oxidases such as enzyme 1 (LOXL1), a key player regulating the assembly of these two elements. This complex is then presented to the fibroblast by Fibulin 5 (FBLN5) that connects the complex to integrins that connect to fibroblasts.14-16 TriHex (palmitoyl tripeptide- 1 and palmitoyl hexapeptide-12) clear the extracellular matrix of aggregated fragmented collagen and elastin and then stimulate increased new collagen and elastin production.9,17 Acetyl tetrapeptide-2 increases FBLN5 and LOXL1 protein levels, thereby increasing elastin synthesis. It also upregulates genes related to collagen 1 synthesis. In vivo, it has been shown to reduce parameters linked to skin flaccidity and dermal disorganization. 18 Anethum graveolens (Dill extract) produces a reinduction of LOXL synthesis.15 While microfibrils and soluble elastin continue to be synthesized throughout life, LOXL dramatically decreases from the age of 18. In addition, lactoferrin stimulates tropoelastin synthesis.19,20 As with previous studies, we were able to validate changes taking place at a molecular level involving collagen and elastin in all 4 patients biopsied (Figures 8 and 9). These were early time points (biopsies at 2 weeks after treatment) but even taking that into consideration we were able to demonstrate good early regeneration of collagen and elastin (fibrillin) from topical use of the product. This confirms the advantage of using an adjunctive topical therapy demonstrating synergistic effects on volumization at a molecular level.
Intrinsic hyaluronic acid (HA) stimulation
The promotion of intrinsic HA stimulation is extremely advantageous over extrinsic addition of HA products. This is important as many topical preparations use combinations of high and low molecular weight (MW) HA to promote skin hydration. However, in the wound healing literature, low MW HA is known to be very pro-inflammatory and should be avoided whenever possible when treating the skin.21 That leaves high MW HA that is very efficient in treating the skin surface but cannot penetrate the skin depth to the dermis. It seems logical then to combine a high MW HA together with agents that stimulate the fibroblast to produce more HA in the depths of the skin. Hydroxymethoxyphenyl decanone is a potent hyaluronic acid booster, antioxidant, and anti-irritant. It has been demonstrated to stimulate the dermal and epidermal hyaluronic acid level by 259% and 198% versus placebo, respectively, in an ex vivo human skin model.22 Tremella fuciformis extract (from edible white fluffy mushroom) serves as a natural hyaluronic acid providing very high levels of moisture and anti-oxidant properties.23,24 Lactoferrin has wound healing attributes, promotes proliferation of fibroblasts and increases HA secretion.25,26 Aside from intrinsic HA stimulation, sodium hyaluronate crosspolymer is a chemically crosslinked hyaluronic acid derived from a non-animal source. It possesses an exceptionally high water-binding capacity resulting in excellent moisturizing abilities.
Adipocyte stimulation – adipogenesis
Newer studies suggest that fillers may stimulate de novo adipogenesis by mechanical stimulation of adipose stem cells possibly in the dermal white adipose tissue layer.27 This layer sits at a level above the subcutaneous white adipose layer, has direct contact with dermal papilla cells and is an area where follicular stem cells and adipose stem cells appear to engage in cross talk.27 In addition, acetyl hexapeptide 38 peptide is a PGC1a stimulator (peroxisome proliferator-activated receptorgamma— PPARγ—coactivator 1 alpha). PGC1a plays a central role in adipogenic activity.28 PGC1a strongly induces differentiation of preadipocytes into white adipocytes under the influence of PPARγ. The young adipocytes formed under these condi-
Additional Benefits Related to Active Ingredients in Topical Product: Volumetric Enhancement and Regeneration
Elastin (and collagen) stimulation synergy with fillers (Figure 8 and Figure 9)
Elastin is an assembly of microfibrils and tropoelastin (or soluble elastin). Elastin fibers are formed first by the synthesis of fibrillin microfibers that intertwine and then associate with tropoelastin (TE) protein molecules. TE molecules are bound together and cross-linked together with fibrillin fibers by lysyl oxidases such as enzyme 1 (LOXL1), a key player regulating the assembly of these two elements. This complex is then presented to the fibroblast by Fibulin 5 (FBLN5) that connects the complex to integrins that connect to fibroblasts.14-16 TriHex (palmitoyl tripeptide- 1 and palmitoyl hexapeptide-12) clear the extracellular matrix of aggregated fragmented collagen and elastin and then stimulate increased new collagen and elastin production.9,17 Acetyl tetrapeptide-2 increases FBLN5 and LOXL1 protein levels, thereby increasing elastin synthesis. It also upregulates genes related to collagen 1 synthesis. In vivo, it has been shown to reduce parameters linked to skin flaccidity and dermal disorganization. 18 Anethum graveolens (Dill extract) produces a reinduction of LOXL synthesis.15 While microfibrils and soluble elastin continue to be synthesized throughout life, LOXL dramatically decreases from the age of 18. In addition, lactoferrin stimulates tropoelastin synthesis.19,20 As with previous studies, we were able to validate changes taking place at a molecular level involving collagen and elastin in all 4 patients biopsied (Figures 8 and 9). These were early time points (biopsies at 2 weeks after treatment) but even taking that into consideration we were able to demonstrate good early regeneration of collagen and elastin (fibrillin) from topical use of the product. This confirms the advantage of using an adjunctive topical therapy demonstrating synergistic effects on volumization at a molecular level.
Intrinsic hyaluronic acid (HA) stimulation
The promotion of intrinsic HA stimulation is extremely advantageous over extrinsic addition of HA products. This is important as many topical preparations use combinations of high and low molecular weight (MW) HA to promote skin hydration. However, in the wound healing literature, low MW HA is known to be very pro-inflammatory and should be avoided whenever possible when treating the skin.21 That leaves high MW HA that is very efficient in treating the skin surface but cannot penetrate the skin depth to the dermis. It seems logical then to combine a high MW HA together with agents that stimulate the fibroblast to produce more HA in the depths of the skin. Hydroxymethoxyphenyl decanone is a potent hyaluronic acid booster, antioxidant, and anti-irritant. It has been demonstrated to stimulate the dermal and epidermal hyaluronic acid level by 259% and 198% versus placebo, respectively, in an ex vivo human skin model.22 Tremella fuciformis extract (from edible white fluffy mushroom) serves as a natural hyaluronic acid providing very high levels of moisture and anti-oxidant properties.23,24 Lactoferrin has wound healing attributes, promotes proliferation of fibroblasts and increases HA secretion.25,26 Aside from intrinsic HA stimulation, sodium hyaluronate crosspolymer is a chemically crosslinked hyaluronic acid derived from a non-animal source. It possesses an exceptionally high water-binding capacity resulting in excellent moisturizing abilities.
Adipocyte stimulation – adipogenesis
Newer studies suggest that fillers may stimulate de novo adipogenesis by mechanical stimulation of adipose stem cells possibly in the dermal white adipose tissue layer.27 This layer sits at a level above the subcutaneous white adipose layer, has direct contact with dermal papilla cells and is an area where follicular stem cells and adipose stem cells appear to engage in cross talk.27 In addition, acetyl hexapeptide 38 peptide is a PGC1a stimulator (peroxisome proliferator-activated receptorgamma— PPARγ—coactivator 1 alpha). PGC1a plays a central role in adipogenic activity.28 PGC1a strongly induces differentiation of preadipocytes into white adipocytes under the influence of PPARγ. The young adipocytes formed under these condi-
