Cosmetic composition

Abstract

The invention relates to a composition comprising, based on the total weight of the composition: - a first glycosaminoglycan or a derivative thereof having a molar mass Mn of less than or equal to 100 kDa, preferably comprised between 10 and 100 kDa, preferably between 15 and 100 kDa, more preferably between 15 and 50 kDa; - a second glycosaminoglycan or a derivative thereof having a molar mass Mn greater than 100 kDa preferably comprised between 100 kDa and 3000 kDa, preferably between 150 and 2500 kDa, preferably between 500 and 2000 kDa; - a penetration enhancer; an organosilicon compound stabilized with rhamnose

Description

[0001] Cosmetic composition

[0002] Technical Field

[0003] The present invention relates to a composition comprising two hyaluronic acid, a penetration enhancer and an organosilicon compound stabilized by a rhamnose and the use thereof in cosmetic and / or dermatological applications, such as to enhance the production of elastin and collagen, to activate the fibroblast growth factor expression, to prevent and repair cutaneous aging, and for cell reparation.

[0004]

[0005] of the invention

[0006] Fibroblast growth factors (FGF), for example FGF1 , FGF2, FGF7, FGF9 and FGF10, play a significant role in dermal fibroblasts and the ageing process. A natural decline in FGF is observed during ageing leading to a reduction in the capacity of dermal fibroblasts to produce the extracellular matrix. The induction of FGF expression may prevent the skin matrix decline linked to the ageing process. The dermis fibroblasts is one of the major sources of secretion of FGF factor.

[0007] The dermis extracellular matrix plays a crucial role in skin aging as it provides structural support, elasticity and hydration to skin. Overtime, changes in the composition and organization of the dermal matrix, including a reduction in collagen and elastin fibers, contribute to the development of wrinkles, sagging and loss of skin firmness.

[0008] There is thus a need to provide a composition that enables both to promote the expression of FGF in dermis fibroblast and to promote the expression of matrix protein in human skin fibroblast and especially collagen 1, collagen 3, laminin, elastin and fibrillin. There is a need to provide such composition for topical application.

[0009]

[0010] of the invention

[0011] Unexpectedly, it has now been discovered that by combining two glycosaminoglycan with a penetration enhancer and an organosilicon compound stabilized by a rhamnose it is possible to penetrate the skin untilthe surperficial dermis and to promote both the expression of FGF in dermis fibroblast and the expression of matrix protein in human skin fibroblast and especially collagen 1, collagen 3, laminin, elastin and fibrillin. It has been discovered that this association enables to prevent and repair cutaneous aging, and can also be used for stimulation of cell metabolism.

[0012] This composition, that is a composition for topical application, synergistically promotes the expression of FGF and the expression of matrix protein in human skin fibroblast and especially collagen 1, collagen 3, laminin, elastin and fibrillin.

[0013] The invention relates to a composition comprising, based on the total weight of the composition:

[0014] - a first glycosaminoglycan or a derivative thereof having a molar mass Mn of less than or equal to 100 kDa, preferably comprised between 10 and 100 kDa, preferably between 15 and 100 kDa, more preferably between 15 and 50 kDa;

[0015] - a second glycosaminoglycan or a derivative thereof having a molar mass Mn greater than 100 kDa preferably comprised between 100 kDa and 3000 kDa, preferably between 150 and 2500 kDa, preferably between 500 and 2000 kDa;

[0016] - a penetration enhancer;

[0017] an organosilicon compound stabilized with rhamnose

[0018] Preferably, the invention relates to a composition comprising, based on the total weight of the composition:

[0019] - from 0.1 to 10wt%, preferably from 0.1 to 5 wt%, more preferably from 0.1 to 0.5 wt%, preferably from 0.15 to 0.3 wt%, of a first glycosaminoglycan or a derivative thereof having a molar mass Mn of less than or equal to 100 kDa, preferably comprised between 10 and 100 kDa, preferably between 15 and 100 kDa, more preferably between 15 and 50 kDa;

[0020] - from 0.1 to 10 wt%, preferably from 0.1 to 5 wt%, more preferably from 0.1 to 0.3 wt%, preferably from 0.15 to 0.2 wt%, of a second glycosaminoglycan or a derivative thereof having a molar mass Mn greater than 100 kDa, preferably comprised between 100 kDa and 3000 kDa, preferably between 150 and 2500 kDa, preferably between 500 and 2000 kDa;- from 0.1 to 10 wt%, preferably from 0.1 to 5 wt%, more preferably from 0.1 to 0.5 wt%, preferably from 0.2 to 0.3 wt%, of a penetration enhancer;

[0021] - from 0.05 to 5 wt%, preferably from 0.05 to 2 wt%, more preferably from 0.05 to 0.2 wt%, preferably from 0.1 to 0.11 wt%, of an organosilicon compound stabilized with rhamnose.

[0022] Preferably, the glycosaminoglycan is selected for hyaluronic acid or a salt thereof, chondroitin sulfate and keratan sulfate and is preferably hyaluronic acid or sodium hyaluronate.

[0023] Preferably, the glycosaminoglycan is a non-crossl inked glycosaminoglycan, preferably is a non-crossl inked hyaluronic acid or salt thereof.

[0024] Preferably, the penetration enhancer is a lecithin based penetration enhancer.

[0025] Preferably, the glycosaminoglycan is a hyaluronic acid or a derivative thereof or a salt of hyaluronic acid or a derivative thereof and is preferably a non-crosslinked hyaluronic acid, derivative or salts thereof.

[0026] Preferably, the composition is under the form of a cream, a serum, a mask, an essence.

[0027] Preferably, the composition further comprising at least one additive chosen among preservatives, antioxidants, thickening and stabilizing agents, emulsifiers, humectants, texture enhancers, fragrances, chelating agents, or a mixture thereof.

[0028] Preferably, the weight ratio organosilicon compound / total amount of glycosaminoglycan is comprised between 0.01 and 0.5, preferably between 0.03 and 0.25, preferably between 0.03 and 0.15, preferably between 0.05 and 0.1.

[0029] Preferably, the first glycosaminoglycan is a derivative hyaluronic acid, preferably a salt of a derivative hyaluronic acid, preferably sodium acetylated hyaluronate.Preferably, the second glycosaminoglycan is a salt of hyaluronic acid, preferably sodium hyaluronate.

[0030] The invention also relates to a cosmetic use of the composition for reducing wrinkles, and for stimulation of cell metabolism.

[0031] The invention also relates to a cosmetic use of the composition for promoting both the expression of FGF in dermis fibroblast and the expression of matrix protein in human skin fibroblast and especially collagen 1, collagen 3, laminin, elastin and fibrillin.

[0032] Detailed

[0033]

[0034] The invention is now described in more detail and in a non-limiting manner in the following description.

[0035] All concentrations are expressed by weight unless otherwise specified.

[0036]

[0037] stabilized by Rhamnose

[0038] The composition of the invention includes an organosilicon compound of formula (I) : RxSi(OH)4-x, or a salt thereof, wherein each R is independently a group containing from 1 to 20 carbon atoms (alkyl, alkenyl or aryl, preferably alkyl) and x = 1 to 3.

[0039] In preferred variations, x=1 or 2, and the organosilicon compound is a diol or a triol. Preferably, in the present invention x is 1 and the organosilicon compound is a triol.

[0040] Each R may contain only carbon or hydrogen, or may optionally contain one or more heteroatoms, such as oxygen, sulfur, or nitrogen. Preferably, R does not contain silicon.

[0041] Each R may be have a linear, branched or cyclic structure.

[0042] Preferably, each R contains from 1 to 10 carbon atoms.

[0043] Each R may be notably selected from the following groups: alkyl, substituted alkyl, alkenyl group, substituted alkenyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio,substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C3-C20 cyclic, substituted C3-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups.

[0044] In preferred variations, each R is independently selected from (C1-C4)alkyl, (C2-C6)alkenyl, (C6-C10)aryl, (C1-C6)alkyl-(C6-C10)aryl.

[0045] In preferred variations, each R is independently selected from (C1-C4)alkyl, preferably from (C1-C3)alkyl, more preferably from (C1-C2)alkyl, even more preferably is methyl.

[0046] When more than one R is present, they may be identical or different, preferably identical.

[0047] Preferably, the organosilicon compound is monomethylsilanetriol.

[0048] The organosilicon compound if stabilized by Rhamnose, i.e. each OH group of the organosilicon compound is stabilized by a Rhamnose.

[0049] Preferably, the organosilicon compound is a monomethylsilanetriol stabilized by three Rhamnose.

[0050] In the present invention, “an OH group stabilized by a Rhamnose” is an OH group chemically linked to a Rhamnose.

[0051] Such compounds are described in EP1750770.

[0052] Advantageously, such compound promotes the expression of hyaluronic acid.

[0053]

[0054] The composition of the invention comprises two glycosaminoglycans. The first glycosaminoglycan has a having a molar mass Mn of less than or equal to 100 kDa, preferably comprised between 10 and 100 kDa, preferably between 15 and 100 kDa, more preferably between 15 and 50 kDa; and the second glycosaminoglycan has a molar mass Mn greater than 100 kDa,preferably comprised between 100 kDa and 3000 kDa, preferably between 150 and 2500 kDa, preferably between 500 and 2000 kDa .

[0055] It should be understand that the molar mass Mn of the first glycosaminoglycan is lower than the molar mass Mn of the second glycosaminoglycan.

[0056] The Mn is measured by SEC chromatography and GPC.

[0057] Advantageously, the first glycosaminoglycan having a low molar mass penetrates more deeply in the skin enabling a deeply hydration and a targeted action on the deep skin layers. Advantageously, the second glycosaminoglycan having a greater molar mass forms a moisturizing film enabling to preserving the hydration while providing protective and anti-ageing effects.

[0058] Glycosaminoglycan is a polysaccharide comprising repeating disaccharide units, each disaccharide unit consisting of an amino sugar and a non-amino sugar.

[0059] The non-amino sugar may be in particular a uronic sugar or galactose. The amino sugar may be in particular N-acetyl-glucosamine.

[0060] The glycosaminoglycan may be in the form of a salt or not.

[0061] Glycosaminoglycans include, in particular, heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid.

[0062] Preferred is hyaluronic acid (also known as hyaluronan), derivative of hyaluronic acid or a salt thereof, such as sodium hyaluronate.

[0063] Preferably the hyaluronic acid is non-crosslinked, also known as free hyaluronic acid.

[0064] A derivative of hyaluronic acid is for example an acetylated hyaluronic acid or a salt thereof.

[0065] Preferably, the first glycosaminoglycan is a derivative hyaluronic acid, preferably a salt of a derivative hyaluronic acid, preferably sodium acetylated hyaluronate.

[0066] Preferably, the second glycosaminoglycan is a salt of hyaluronic acid, preferably sodium hyaluronate.

[0067] Preferably, the weight ratio between the first and the second glycosaminoglycan is comprised between 0.5 and 1.5, preferably between 0.7 and 1.Penetration enhancer

[0068] The penetration enhancer is a compound that enables the compounds of the composition to penetrates until the superficial dermis to promote both the expression of FGF in dermis fibroblast and the expression of matrix protein in human skin fibroblast and especially collagen 1, collagen 3, laminin, elastin and fibrillin.

[0069] Several penetration enhancer are known from the skilled person and can be used in the present invention.

[0070] Such penetration enhancer can be for example liposome or nanoparticles, lipides and solvents such as propylene glycol, ethanol, butylene glycol, glycerin, surfactant such as polysorbates and lecithin or lecithin derivatives, essential oils and vegetable oils such as menthol, terpenes (such as limonene, cineole), jojoba oil, argan oil, almond oil, acid such as salicylic acid, glycolic acid, oleic acid, urea, dimethylsulfoxide. Preferably the penetration enhancer is a lecithin based penetration enhancer, such as lysolecithine.

[0071] Additives

[0072] The composition according to the present invention can further comprises any usual additives commonly used in cosmetic composition for topical applications.

[0073] For example, the additives can be chosen among solvent (such as for example triglyceride (caprylic triglyceride), alkane from C15 to C19, pentylene glycol, propanediol), moisturizer, texturizing agent, preservatives, antioxidants, thickening and stabilizing agents, emulsifiers, humectants, texture enhancers, fragrances, chelating agents, or a mixture thereof.

[0074] The total amount of additives, in the composition of the invention, is comprised between 5 and 45 wt%, preferably between 10 and 45 wt%, preferably between 20 and 45 wt%, preferably between 25 and 40 wt%.

[0075] For example, the mixture of additive can be a mixture of solvent moisturizer and texturing agent, humectant, emulsifier, thickening and stabilizing agent, fragrance , antioxidants, preservatives, chelating agent.Composition

[0076] More preferably, the composition of the invention may comprise:

[0077] the first glycosaminoglycan in an amount from 0.1 to 0.5 wt%, preferably from 0.15 to 0.3 wt%,

[0078] the second glycosaminoglycan in an amount from 0.1 to 0.3 wt%, preferably from 0.15 to 0.2 wt%,

[0079] the organosilicon compound stabilized by rhamnose in an amount from 0.05 to 0.2 wt%, preferably from 0.1 to 0.11 wt%, the penetration enhancer in an amount from 0.1 to 0.5 wt%, preferably from 0.2 to 0.3 wt%.

[0080] The total amount of additives, in the composition of the invention, is preferably comprised between 20 and 45 wt%, preferably between 25 and 40 wt%.

[0081] Preferably the weight ratio organosilicon compound / total amount of glycosaminoglycan is comprised between 0.01 and 0.5, preferably between 0.03 and 0.25, preferably between 0.03 and 0.15, preferably between 0.05 and 0.1. It should be understood that the amount of rhamnose is not taken into account in this ratio.

[0082] The composition comprises water, preferably water qsp 100% (i.e. the complement to 100 wt% in the composition is water).

[0083] The composition according to the invention is for topical application, preferably under the form of a cream, a serum, a mask, an essence, preferably a cream.

[0084] The composition of the present invention can be prepared by any method known from the skilled person and especially by mixing the different compounds.

[0085] Use of the composition

[0086] The composition can be used for cosmetic and / or dermatological purposes.The invention relates to a cosmetic use of the composition for reducing wrinkles and for stimulation of cell metabolism. This cosmetic use if non therapeutical.

[0087] The composition according to the invention is for topical application.

[0088] Preferably, the composition according to the invention is administered locally, in the region of the face, in particular of the nasolabial folds, of the periorbital zone, of the contour of the lips, of the forehead and of the area between the eyebrows, in the region of the neck and / or in the neckline area.

[0089] The composition can be used in particular to treat wrinkles, fine lines, fibroblast depletions and scars; or to prevent wrinkles, fine lines and fibroblast depletions.

[0090] The composition makes it possible to promote both the expression of FGF in dermis fibroblast and the expression of matrix protein in human skin fibroblast and especially collagen 1, collagen 3, laminin, elastin and fibrillin.

[0091] The composition makes it possible to hydrate the skin.

[0092] The composition makes it possible to improve the condition of the skin. The composition makes to reduce or prevent signs of skin aging, especially UV-induced skin aging, the composition also enables to reduce wrinkles. The composition is also useful for and for stimulation of cell metabolism.

[0093] The invention thus relates to a method of cosmetic treatment comprising a step of administering the composition to a subject by topical application.

[0094] Examples

[0095] The following examples illustrate the invention without limiting it.

[0096] Composition according to the invention:The following composition C according to the invention is prepared by mixing of the following ingredients (the proportion are given in weight based in the total weight of the composition):

[0097] - 0.15 wt% of sodium hyaluronate having a molar mass Mn of between 1000 and 2000 kDa;

[0098] - 0.25 wt% of sodium hyaluronate having a molar mass Mn of between 20 and 50 kDa;

[0099] - 0,20 wt% of lysolecithine;

[0100] - 0,125 wt% of silanetriol stabilized by Rhamnose (0,016 wt% of silanetriol and 0,109 wt% of rhamnose);

[0101] - 40 wt% of additives

[0102] - Qsp water.

[0103] The culture medium, in the below assays, comprises 20% of FBS (Fetal bovine serum) in Dulbecco's Modified Eagle Medium (DMEM).

[0104] Protocol for cell culture

[0105] Human fibroblast cells are sourced from three different donors. These cells are cultured, amplified and grown for 2 weeks to ensure there is an adequate number of cells for the experiment.

[0106] Protocol for in vitro cytotoxicity tests

[0107] The amplified cells are then seeded into 96-well plates. The cells are kept in these plates for 1 week to allow them to adhere and grow.

[0108] After the initial incubation period, the cells are exposed to different doses for 24 hours. These doses are likely varying concentrations of the composition according to the invention being tested to observe its effect in the human fibroblast cells.

[0109] A cytotoxicity test is performed one week after exposure to the doses. This test corresponds to the lactate dehydrogenase (LDH) activity measurement. The LDH assay measures the amount of LDH enzyme released into the culture medium indicating membrane damage due to cytotoxicity of the testes compound. High LDH activity indicates high cytotoxicity (cell damage).

[0110] Protocol for FGF2 Expression analysis

[0111] The amplified cells are then seeded into 12-well plates. The cells are then cultured for 1 week until they reach about 90% confluency (i.e. the cellscover about 90% of the plate surface area). Then the cells are treated for 24 hours with two selected doses of the composition according to the invention. After the 24-hour treatment, the cells are harvested (collected) for analysis. After harvesting, a qRT-PCR (quantitative Reverse Transcription Polymerase Chain Reaction) analysis is performed to measure the expression of FGF2 (Fibroblast Growth Factor 2) and GAPDH (a housekeeping gene commonly used as a control for normalization). The qRT-PCR allows for precise quantification of FGF2 expression in treated cells, and the results can be compared to GAPDH expression to understand if and how the cream treatment influences FGF2 expression.

[0112] Protocol for Immunofluorescence

[0113] The amplified cells are then seeded into 96-well plates. The cells are then cultured until they reach about 70% confluency (i.e. the cells cover about 70% of the plate surface area). Then the cells are treated for 72 hours with two selected doses of the composition according to the invention. The culture medium was changed every 1-2 days during the culture period. All conditions were performed in triplicate.

[0114] After the 72-hours treatment period, the cells were fixed using 4% paraformaldehyde to preserve cell structure. The fixed cells were then washed with PBS (Phosphate-Buffered Saline) to remove any excess fixative.

[0115] Specific antibodies were used to stain the extracellular matrix proteins (Collagen I, Collagen III, Laminin, Elastin, and Fibrillin). The staining process was carried out at 4°C overnight to allow for proper binding of antibodies. A DAPI (4',6-diamidino-2-phenylindole) staining was performed at room temperature to stain the nuclei of the cells, allowing for visualization of cell position.

[0116] Images were acquired using an automated fluorescent microscope, capturing the fluorescence signals from the specific antibodies (for matrix proteins) and the DAPI staining (for nuclei).

[0117] The acquired images were processed using a specific algorithm that calculated:

[0118] - Total surface area covered by the matrix fibers (e.g., collagen, elastin); and

[0119] - Number of cells based on DAPI-stained nuclei.

[0120] Results

[0121] The results of the above experiments are given in the below table.Table 1

[0122]

[0123] Table 2 - Gene expression analysis

[0124]

[0125] Table 3 - Collagen I

[0126]

[0127] Table 4 - Collagen 3

[0128]

[0129] Table 5 - Laminin

[0130]

[0131] Table 6 - Elastin

[0132]

[0133] Table 7 - Fibrillin

[0134]

[0135] These results show that the composition according to the invention enables to promote both the expression of FGF in dermis fibroblast and the expression of collagen 1, collagen 3, laminin, elastin and fibrillin.

Claims

Claims1. A composition comprising :- a first glycosaminoglycan or a derivative thereof having a molar mass Mn of less than or equal to 100 kDa, preferably comprised between 10 and 100 kDa, preferably between 15 and 100 kDa, more preferably between 15 and 50 kDa;- a second glycosaminoglycan or a derivative thereof having a molar mass Mn greater than 100 kDa preferably comprised between 100 kDa and 3000 kDa, preferably between 150 and 2500 kDa, preferably between 500 and 2000 kDa; - a penetration enhancer;- an organosilicon compound stabilized with rhamnose.

2. A composition according to claim 1 comprising:from 0.1 to 10wt%, preferably from 0.1 to 5 wt%, more preferably from 0.1 to 0.5 wt%, preferably from 0.15 to 0.3 wt%, of a first glycosaminoglycan or a derivative thereof having a molar mass Mn of less than or equal to 100 kDa, preferably comprised between 10 and 100 kDa, preferably between 15 and 100 kDa, more preferably between 15 and 50 kDa;from 0.1 to 10 wt%, preferably from 0.1 to 5 wt%, more preferably from 0.1 to 0.3 wt%, preferably from 0.15 to 0.2 wt%, of a second glycosaminoglycan or a derivative thereof having a molar mass Mn greater than 100 kDa, preferably comprised between 100 kDa and 3000 kDa, preferably between 150 and 2500 kDa, preferably between 500 and 2000 kDa;from 0.1 to 10 wt%, preferably from 0.1 to 5 wt%, more preferably from 0.1 to 0.5 wt%, preferably from 0.2 to 0.3 wt%, of a penetration enhancer;from 0.05 to 5 wt%, preferably from 0.05 to 2 wt%, more preferably from 0.05 to 0.2 wt%, preferably from 0.1 to 0.11 wt%, of an organosilicon compound stabilized with rhamnose.

3. A composition according to claim 1 comprising :- from 0.1 to 0.5 wt%, preferably from 0.15 to 0.3 wt%, of a first glycosaminoglycan or a derivative thereof having a molar mass Mn of less than or equal to 100 kDa, preferably comprised between 10and 100 kDa, preferably between 15 and 100 kDa, more preferably between 15 and 50 kDa;- from 0.1 to 0.3 wt%, preferably from 0.15 to 0.2 wt%, of a second glycosaminoglycan or a derivative thereof having a molar mass Mn greater than 100 kDa, preferably comprised between 100 kDa and 3000 kDa, preferably between 150 and 2500 kDa, preferably between 500 and 2000 kDa;- from 0.1 to 0.5 wt%, preferably from 0.2 to 0.3 wt%, of a penetration enhancer;- from 0.05 to 0.2 wt%, preferably from 0.1 to 0.15 wt%, of an organosilicon compound stabilized with rhamnose.

4. A composition according to any one of the preceding claims, wherein the penetration enhancer is chosen among lecithin based penetration enhancer.

5. A composition according to any one of the preceding claims, wherein the glycosaminoglycan is a hyaluronic acid or a derivative thereof or a salt of hyaluronic acid or a derivative thereof and is preferably a non-crossl inked hyaluronic acid, derivative or salts thereof.

6. A composition according to any one of the preceding claims, wherein the composition is under the form of a cream, a serum, a mask, an essence.

7. A composition according to any one of the preceding claims, further comprising at least one of preservatives, antioxidants, thickening and stabilizing agents, emulsifiers, humectants, texture enhancers, fragrances, chelating agents, or a mixture thereof.

8. A composition according to any one of the preceding claims, wherein the weight ratio organosilicon compound / total amount of glycosaminoglycan is comprised between 0.01 and 0.5, preferably between 0.03 and 0.25.

9. A composition according to any one of the preceding claims, wherein the weight ratio organosilicon compound / total amount of glycosaminoglycan is comprised between preferably between 0.03 and 0.15, preferably between 0.05 and 0.1.

10. A composition according to any one of the preceding claims, wherein the weight ratio between the first and the second glycosaminoglycan is comprised between 0.5 and 1.5, preferably between 0.7 and 1.

11. A composition according to any one of the preceding claims, wherein the second glycosaminoglycan is a salt of hyaluronic acid, preferably sodium hyaluronate.

12. A composition according to any one of the preceding claims, wherein the first glycosaminoglycan is a derivative hyaluronic acid, preferably a salt of a derivative hyaluronic acid, preferably sodium acetylated hyaluronate.

13. Cosmetic use of a composition according to any one of claims 1 to 12 for reducing wrinkles, and for stimulation of cell metabolism.

14. Cosmetic use of a composition according to any one of claims 1 to 12 for promoting both the expression of FGF in dermis fibroblast and the expression of matrix protein in human skin fibroblast and especially collagen 1, collagen 3, laminin, elastin and fibrillin.

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