During last decade, lots of companies developed new generation of skin care products based on the research and development (R&D) section. This new generation, rely on the power of peptides and mixture of proteins comes from different cells. Some of the countries such as: United States, China, South Korea and India trying to make change on the regulatory section to make this product available in the market. However, it seems European countries still confined marketing of them due to their sources which is human. It should be noted that, all of these products meet the scientific & functional assays to prove better efficiency in different publications. This is the reason that industries tend to use regenerative medicine and biotechnology products in this field.  In this review, we try to provide update categorized data; show different aspect of this science based on the available products, and make them more understandable for medical section and regulatory infrastructure. Moreover, we will look for the update research article, clinical trial and case studies with using this new knowledge. We believe this information would be helpful for the design of new research in the R&D sector, development and manufacturing new products in the companies and even clinicians. After reviewing of different search engine (such as Google, Bing and Yandex), digital marketing network (such as Amazon and eBay) and publications (PubMed and Clinicaltrial.gov), with the specific keywords (cosmeceutical products, skin care, rejuvenation, anti-wrinkle, anti-aging, anti-hair loss in combination with growth factor, peptide, protein, conditioned medium and cell-derivate), second filtration have been done to categorized data and discarded products claimed related words but not actually used. Finally, we found 200 products from 85 companies which is divided to two main section:

• skin cares that used conditioned medium (mostly from human source) as mixture of protein and growth factors
• products that used growth factors or/and multi-peptides (derived from plant, human or bacterial (biotechnology process)

In 2007, Regenerative medicine was defined [1] as interdisciplinary field which is involved:

• Stem cell biology like using the power of stem cell to repair or enhance regeneration in specific purpose
• Tissue engineering which means applying the principles of engineering, with suitable material and cells to restore, maintain, or improve tissue function [2]
• Material science, as a part of tissue engineering or independently, by using new technology such as 3D printing to make a new organ for transplantation [2]
• Genetic and molecular biology, such as using genetic engineering to manipulate cells for curing diseases or utilize small bioactive molecules, protein, growth factor (GFs), peptides or even amino acids to regenerate or promote tissue/ organ function. Biotechnology and nanotechnology also could be considered in this part.
• Cell, tissue and organ transplantation, which could be related to all fields mentioned above by auto or allo- transplanting stem cells, organs or tissues, and small molecules
• Developmental biology, like studying physical, chemical, and electrical cues that define the micro-environmental niche and the effect of these influences upon cell behavior during development [3]

Increasing number of studies and therapeutic approaches comes from regenerative medicine and stem cell therapy led to industries, especially, R&D section design wide variety of clinical trials and further products to satisfy consumer by better efficacy. It has been reported [4] Richard Fitzpatrick and Elizabeth Rostan from USA, for the first time described topical application of GFs in 2003 which is resulted in collagen formation, epidermal thickening and the clinical appearance of smoother skin with less visible wrinkling after photo damage[5]. It is challengeable to find the exact time of the cosmeceutical companies start using regenerative medicine derived components as ingredient since they prefer to keep data as patent instead of publication, but it seems SkinMedica TNS Recovery Complex is the first commercially available cosmetic product containing human growth factors, which was developed by Naughton (Allergan, the company that owns SkinMedica® and Regenica® production line) in the ‘90s [6]. Afterwards and in last decade, some of the countries like USA and South Kore lunched lots of products derived human cell or stem cells factors. Although, there are variety of sources which used as cosmetic ingredients such as: biological, marine, herbal, synthetic, animal and human. The efficacy of these materials depends to different combination which used for the formulation. The proper formulation and physical shape could delivered expected aesthetic effect to the consumers [7].

Reviewing the cosmeceutical products contain growth factor or mixture of growth factors like conditioned medium (CM), showed that mesenchymal stem cell, especially adipose and bone marrow derived conditioned medium used as ingredient more than fibroblast and fetal derived sources (such as placenta, cord blood and the fetal stem cells) (Fig1-C). In addition, growth factors like EGF, FGF, IGF and HGF used more than other growth factors such as PDGF, VEGF, KGF and TGF-beta. Although, the level of growth factors secretion depends to the medium used for cultivation [8] and even culture condition [9]; but in general, several studies showed translation of CM into clinic or industries. It should be noted that conditioned medium used as mixture of GFs so in below, we discussed the main GFs secreted by ADSC, BMSC and Fibroblast cells which is also indicate direct role of each GF, separately.  Review study by Pawitan in 2014, listed the most important GFs secreted by stem cells [9]. From various analysis study, he concluded VEGF, Is the most frequent stem cell (SC) growth factor secretion. VEGF play important role in angiogenesis to recover injuries. Besides, some of the critical GFs secreted by different SC such as: FGF2, EGF, HGF, PlGF, SDF-1, PDGF, TGFβ1 and PDEGF have specific role in proliferation, migration, and differentiation. Taken together, the most important GFs produce by adipose derived SC (ADSC) are: GCSF, GM-CSF, IGFII, PDGF-AA and Rβ, FGF2, VEGF, EGF and M-CSF [8, 9].  Besides, previous studies showed higher amount of elastin secretion after ADSC-CM treatment [10, 11] (they showed percutaneous absorption after topical application [12], as long as collagen biosynthesis [11, 13] by inhibition of procollagen type I synthesis inhibitor, downregulated the expression of MMP1[14] and MMP9 mRNA[13] and upregulation of collagen synthesis enhancer gene transforming growth factor-β (TGF-β)[12]. In addition, reduction in the level of melanin synthesis through downregulation of tyrosinase and tyrosinase-related protein 1 (TRP1) and presence of TGFβ1 as melanin expression suppressor [11, 15] after ADSC utilization, resulted in whitening effect and decrease erythema level.  In 2019, Li et al, described anti-photo aging mechanism of ADSC through down regulation of MMP-1 and secretion of IL6 (Interleukin 6) by mitogen-activated protein kinase (MAPK) and TGF-β/Smad signaling pathway [16]. Moreover, ADSC treatment have anti-scar effect by inhibition the p38/MAPK signaling pathway [17]. TGF- β1, basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF)-BB, which all secreted from ADSC, could enhance Hyalurunic Acid (HA) production in dermal fibroblast. TGF-β1 have most important role in production of high molecular weight HA by increase HAS (HA synthases) and decrease HYBID ((HYaluronan-Binding protein Involved in hyaluronan Depolymerization), also called KIAA1199 that plays a key role in HA de-polymerization) [18].  The Wnt/ β-catenin signaling pathway can promote the activation of skin fibroblasts through the transplantation of ADSCs [19]. ADSC CM treated ephitial cells, showed reduced level of inflammatory cytokine such as interleukin (IL)-1β, IL-6, IL-10, mRNA levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) were significantly increased, whereas those of vascular endothelial growth factor, matrix metalloproteinase-9 were significantly decreased [20]. Proteomics analysis of human dermal fibroblast conditioned medium (hDFCM) revealed highly expression of ECM proteins such as fibronectin, collagen I and VI, ECM protein 1, Pentraxin-related protein PTX3, and metalloproteinase inhibitor 1 [21] which have important role in wound healing, and cellular processes such as cell migration and proliferation. Expression of 12 anti-aging genes with specific roles in genomic instability, inflammatory response, apoptosis, cytoskeleton regulators, DNA binding, oxidative stress, and transcriptional regulation such as MRLP43, POLRMT, ANXA5, CLU ,WRN, CDKN1C, COL1A1, COL3A1, EP300, CASP1, PDCD6, GSTA1 has been reported by qPCR analysis of DFCM[22]. The DFCM also have role in enhancing keratinocyte proliferation and migration by enhancing attachment [23]. Increased expression of type I pro-collagen through SMAD 2/3 protein upregulation in fibroblast CM-treated hADSCs [24] and reduction in the expression of MMP-1 after applying of DFCM discovered in previous studies[22].  Analysis of CM from BMSCs shown that they secrete VEGF, PDGF, bFGF, EGF, KGF, TGFβ, HGF[20], IL6, PlGF, ADM, VEGF, SDF-1, HGF, DKK-I [9, 25] that VEGF, FGF2 and HGF stimulate human dermal fibroblast migration[8]. VEGF expression is associated with the stimulation of angiogenesis as we mentioned above, fibroblast and endothelial cell proliferation by activating MAPK pathway [26]; inhibition of apoptosis through activation of protein kinase B, re-epithelialization, and finally collagen deposition [27, 28], which they all resulted in rejuvenation progress. FGF2 or bFGF which is highly expressed in skin tissue, has pro-angiogenesis and pro-migratory effect[29],  and increase survival and proliferation, migration and potential od differentiation of stem cells[30]. Activated FGFRs phosphorylate specific tyrosine residues that lead to activating the RAS-MAPK, phosphatidylinositol 3?kinase (PI3K)/protein kinase B (AKT), Phosphoinositide phospholipase C (PLC)γ, and STAT intracellular signaling pathways. All these signals could be triggered proliferation, survival, differentiation and migration of cells, especially fibroblasts (4, 28). FGF2 treatment enhanced the activity of c-Jun N-terminal kinase (JNK), a key regulator of fibroblast cell migration [31]. EGF stimulates fibroblasts to synthesize increased amount of VEGF and HGF as pro-angiogenesis factors and also increase keratinocyte and fibroblast proliferation [32]. Binding the EGF to EGFR, activate downstream signaling cascade, including Ras/MAPK, PLCγ/PKC, PI3K/Akt, and STAT, which they lead to migration, proliferation, cytoprotection, and  epithelial–mesenchymal transition (EMT)[27]. IGF-1 (through PI3K pathway) and EGF (by activating MAPK pathway) can influence the keratinocyte migration machinery that determines the speed of re-epithelialization and keratinocyte contraction [33]. EGF, formulated in skin care product assessed to show the ability of fibroblast cytokine production [32]. HGF, a factor with angiogenic, anti-apoptotic and immune modulating activity [9], is a cytokine accelerate skin healing process by promoting the dedifferentiation of epidermal cells through ?1-integrin/ILK pathway [27]. HGF also facilitates proliferation of epithelial cells as well as vascular endothelial cells [32]. Platelet-derived growth factor (PDGF) has increase angiogenic properties by overexpressing pathways including HIF-1α or Akt signalling in the stem cells [34].

This section trying to show most important clinical results of using different source of GFs or/and CM as mixture of proteins and GFs in different countries for skin rejuvenation, some of these trials have been done by companies. Skin lesions include scar in 77 candidates (mean age of 63.15 years) assessed after using topical gel contain 30 μg/g EGF. The cases has been follow-up for 6 to 20 weeks and the results indicate, effectiveness 8.65, tolerability 9.53, and comfort 8.86 (max = 10) [35]. Topical application of human sourced of 5 GFs contain IGF1, KGF, EGF, SOD1 and bFGF with HA and combination of stem cell conditioned medium (not defined which kind of stem cells), on 23 Korean women, showed significantly improved in periobital wrinkles assessed by visiometer[36]. Barely, human liked EFG serum was evaluated in the clinical study on 29 women, aged 39-75 with mild to severe wrinkle, fine and course rhytids, photodamage, and pigmentation. The results indicated significant improvement in the appearance of fine lines and rhytids, skin texture, pore size, and various dyschromatic conditions apparent within the first month of use, and continuing improvement trends for the duration of the study [37]. The before and after clinical study by using bone marrow derived stem cell conditioned medium (Cutisera^TM) serum on 40 Indian women aged 35 to 60 showed improvement in fine lines, wrinkles, crow’s feet, evenness of skin tone, skin firmness / laxity, hydration of skin, homogeneity of age spots, and visible pores. this study was followed for 90 days and no adverse effect was reported[38]. Another product, Nutrient Solution Recovery Complex (TNS) (SkinMedica, Carlsbad, CA, USA), one of the most important companies in this field regarding the market share and variety of products, considered for 20 subjects for facial rhytides. This product containing a variety of growth factors including VEGF, PDGF-A, G-CSF, HGF, IL-6, IL-8, and TGF-beta[1]. This clinical study compare this product with Cimicifuga racemosa extract (CRS) (Topix Pharmaceuticals, North Amityville, NY, USA) which contain TGFβ1. The result showed both CRS and TNS demonstrate significant success between baseline and 3-month scores but they reported the success of the CRS product is largely attributable to the incorporation of TGF-beta[1][39]. Phaseshift Rapid in vivo Measurement of Skin (PRIMOS) device was applied to assess efficacy of cream containing mixture of growth factors from cultured human fetal fibroblasts, skin surface roughness was shown to significantly decrease between 10% and 18% depending on the roughness parameter after 2 months of twice-daily application [40], 83% of the subject showed an improved average wrinkle score in the eye area, while 50% showed an improved average wrinkle score in the mouth area [41]. Korean product (Neotis SGF61™; Caregen Co. Ltd), contain IGF-1, VEGF, bFGF, aFGF, EGF and TGF-β3 (0.0001% W/W, respectively) applied to evaluated photo-rejuvenation using the CO2 fractional laser on 15 candidate (mean aged 55±2.45 years). They conclude potential of GF for wound healing and even higher concentration to decrease the down time [42].  Different clinical studies in various clinical conditions like scar[43], senile purpura and dermatoporosis[44], hyperpigmentation[45], photo damage[46, 47], under-eye bag[48], radiation dermatitis in cancerous patient[49], leprosy[50] and even non-healing wound [51, 52]showed the beneficial use of topical GF(especially EGF). The plant based active growth factor (ZO^TM) was assessed in another clinical trial on 41 patients, 2D and 3D skin analysis showed increased dermal thickness as early as week 4, which continued through week 12. The biomimetic protein used in this clinical trial upregulate production of collagen and hyaluronic acid, boost GAG production and induce TGFβ expression [53]. Animal derived GFs also showed regeneration [54] and rejuvenation effect. The product named Calecim® multi action cream, prepared by red deer umbilical cord lining stem cell conditioned media which showed increase epidermal cell turnover and stimulate fibroblast function, reducing the appearance of pigmentation, fine lines, and redness, and to restore skin elasticity assessed in clinical setting on 40 healthy subject[55].

Table 1 summarized all the products available in the market around the world by the name of company, name of products; originate countries and clinical index claimed by owner and Figure 1 showed the statistical schematic representation of this table. USA have the biggest market share (more than 50%), and South Korea is the second country with different products contain GFs (Figure 1A). It seems regulatory framework is the main reason of this much available products in this two countries which allow them to advertise and pre-market products contain human sourced GFs easier than other countries. 44% of the companies around the world have finish products contain human GFs, and 32% working with the GFs made by bacterial expression system. More than 55% of the products have human sourced GFs which shows higher clinical efficacy, they mostly expressed by mammalian expression or conditioned medium collected and concentrated from human cells or stem cells (Figure1-B, E). The companies used mesenchymal and adipose derived stem cell conditioned medium in compare with other sources and then, fetal sourced media more than fibroblast CM. Around 10% of companies didn’t mentioned source of conditioned medium that they’ve been used for finished products (Fig1-C). In total, the product contain peptides and growth factors prepared for 11 clinical indication: antiaging, cleansing, Moisturizing and hydration, anti-hair loss, under-eye treatment (puff, darkness and wrinkle), lash enhancer, defoliant, brightening, scar and Lip balm. These products presented in 9 pharmaceutical firms involved serum, cream, solution (powder with soluble water), lotion, mask, foam, gel, toner and balm. After analyzing the skin care products, we found that serum and cream finial physical shape are the most form produced (Fig1-D), so it seems this two type show more stability with growth factor as effective substance. It have been also found Skin Medica Skin care^@ (TNS) has most expensive products which made with human dermal fibroblast CM. Products contain multi-peptides, growth factors and proteins are considered in the variety of awards in recent years, for instance: Easydew DW-EGF double synergy firming ampoule contain medical grade human sourced EGF which is made in South Korea wined anti-aging serum, toner and ampule anti-aging global award, this products marketed in USA as well and Biopelle tensage intensive anti-aging growth factor serum from Ferndale Pharma Group Inc. wined new beauty award in 2019 (56).

As it has been described, in last decade skin care products contain growth factors, multi peptides, cell- derived material and protein widely noticed by research and development section of the market player companies. Tendency of using new area such as regenerative medicine is increasing, It seems that, based on the available product analysis, traditional skin care contain herbal and natural ingredients tend to change toward using human sourced protein regarding the better efficacy. It is recommended that the researcher and companies in this area should pay attention to the use of new generation of ingredients such as exosome along with new technologies to enhance efficiency of delivery system like liposomal transfer of GF and liposomal transfer of nanoparticle, and cross-linking with lipid domain in order to increase transdermal permeability. We have tried to list available products contain conditioned medium (multi-peptides), peptides specifically growth factors and categorized them to three different group with human, plant and bacterial sourced of preparation. It should be noted, regenerative medicine, biotechnology and small molecules science used as multidisciplinary field to prepare this products. In summary, finding new source of the cells and/or stem cells or mammalian expressed growth factors which capable to add new indications in cosmeceutical area could be an effective method to elevate market share. In addition, working on the delivery system with the economic potential of scale-up is required. The side-effect of using GFs or CM based materials also needs to be assessed by different stages of clinical studies regarding the risk of tumor formation, especially in the products used after micro-needling, laser- therapy and hair-transplant. 

The author reports no conflict of interests in this work.

SC: Stem Cells; GF: Growth Factor; CM: Conditioned Medium; R&D: Research and Development; ADSC: Adipose derived stem cells; hDFCM: human Dermal Fibroblast Conditioned Medium; IL6: Interleukin 6; HYBID: Hyaluronan-Binding protein; VEGF: vascular endothelial growth factor; PDGF: platelet-derived growth factor; bFGF: basic fibroblast growth factor; EGF: epidermal growth factor; KGF: keratinocyte growth factor; TGFβ: transforming growth factor β; HGF: hepatocyte growth factor; SDSF1: stromal derived factor-1; MAPK: mitogen-activated protein kinase.

Table 1: The list of products available or under development in the market around the word in the field of growth factors, peptides and conditioned medium as a mixture of protein and growth factors.

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5. Fitzpatrick RE, Rostan EF. Reversal of photodamage with topical growth factors: a pilot study. Journal of cosmetic and laser therapy: official publication of the European Society for Laser Dermatology. 2003; 5: 25-34.
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12. Zhou B-R, Xu Y, Guo S-L, Xu Y, Wang Y, Zhu F, et al. The Effect of Conditioned Media of Adipose-Derived Stem Cells on Wound Healing after Ablative Fractional Carbon Dioxide Laser Resurfacing. BioMed Research International. 2013; 519126.
13. Kim WS, Park SH, Ahn SJ, Kim HK, Park JS, Lee GY, et al. Whitening effect of adipose-derived stem cells: a critical role of TGF-beta 1. Biol Pharm Bull. 2008; 31: 606-10.
14. Li L NH, Hwang E, Wei X, Liu Y, Liu J, et al. . Conditioned medium from human adipose-derived mesenchymal stem cell culture prevents UVBinduced skin aging in human keratinocytes and dermal fibroblasts. . Int J Mole Sci 2019; 21: 49.
15. Li Y, Zhang W, Gao J, Liu J, Wang H, Li J, et al. Adipose tissue-derived stem cells suppress hypertrophic scar fibrosis via the p38/MAPK signaling pathway. Stem Cell Research & Therapy. 2016; 7: 102.
16. Nagaoka A, Yoshida H, Nakamura S, Morikawa T, Kawabata K, Kobayashi M, et al. Regulation of Hyaluronan (HA) Metabolism Mediated by HYBID (Hyaluronan-binding Protein Involved in HA Depolymerization, KIAA1199) and HA Synthases in Growth Factor-stimulated Fibroblasts. J Biol Chem. 2015; 290: 30910-23.
17. Xu X, Wang HY, Zhang Y, Liu Y, Li YQ, Tao K, et al. Adipose-derived stem cells cooperate with fractional carbon dioxide laser in antagonizing photoaging: a potential role of Wnt and beta-catenin signaling. Cell Biosci. 2014; 4: 24.
18. Park GW, Heo J, Kang JY, Yang JW, Kim JS, Kwon KD, et al. Topical cell-free conditioned media harvested from adipose tissue-derived stem cells promote recovery from corneal epithelial defects caused by chemical burns. Scientific Reports. 2020; 10: 12448.
19. Maarof M, Lokanathan Y, Ruszymah HI, Saim A, Chowdhury SR. Proteomic Analysis of Human Dermal Fibroblast Conditioned Medium (DFCM). The Protein Journal. 2018; 37: 589-607.
20. Chowdary SR*, Jing LS, Zolkafil HNM, NUR’ Wabwa ABAZ, Mothar NAB MD, Abdullah MMNAH. Exploring The Potential of Dermal Fibroblast Conditioned Medium on Skin Wound Healing and Anti-Ageing Sains Malaysiana 2019; 48: 637–44.
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22. Hur W, Lee HY, Min HS, Wufuer M, Lee C-w, Hur JA, et al. Regeneration of full-thickness skin defects by differentiated adipose-derived stem cells into fibroblast-like cells by fibroblast-conditioned medium. Stem Cell Research & Therapy. 2017; 8: 92.
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24. Song M, Finley SD. Mechanistic insight into activation of MAPK signaling by pro-angiogenic factors. BMC Systems Biology. 2018; 12:145.
25. Nourian Dehkordi A, Mirahmadi Babaheydari F, Chehelgerdi M, Raeisi Dehkordi S. Skin tissue engineering: wound healing based on stem-cell-based therapeutic strategies. Stem Cell Research & Therapy. 2019; 10: 111.
26. Johnson KE, Wilgus TA. Vascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair. Advances in wound care. 2014; 3: 647-61.
27. Jin S, Yang C, Huang J, Liu L, Zhang Y, Li S, et al. Conditioned medium derived from FGF-2-modified GMSCs enhances migration and angiogenesis of human umbilical vein endothelial cells. Stem Cell Research & Therapy. 2020; 11: 68.
28. Khan S, Villalobos MA, Choron RL, Chang S, Brown SA, Carpenter JP, et al. Fibroblast growth factor and vascular endothelial growth factor play a critical role in endotheliogenesis from human adipose-derived stem cells. Journal of Vascular Surgery. 2017; 65: 1483-92.
29. Song YH, Zhu YT, Ding J, Zhou FY, Xue JX, Jung JH, et al. Distribution of fibroblast growth factors and their roles in skin fibroblast cell migration. Molecular medicine reports. 2016; 14: 3336-42.
30. Yamamoto A, Ohno, H. and Kuroyanagi, Y. Evaluation of Epidermal Growth FactorIncorporating Skin Care Product in Culture Experiment Using Human Fibroblasts. Open Journal of Regenerative Medicine. 2016; 5, 44-54.
31. Haase I, Evans R, Pofahl R, Watt FM. Regulation of keratinocyte shape, migration and wound epithelialization by IGF-1- and EGF-dependent signalling pathways. Journal of cell science. 2003; 116: 3227-38.
32. Merckx G, Hosseinkhani B, Kuypers S, Deville S, Irobi J, Nelissen I, et al. Angiogenic Effects of Human Dental Pulp and Bone Marrow-Derived Mesenchymal Stromal Cells and their Extracellular Vesicles. Cells. 2020; 9.
33. Esquirol-Caussa J, Herrero-Vila E. Human recombinant epidermal growth factor in skin lesions: 77 cases in EPItelizando project. J Dermatolog Treat. 2019; 30: 96-101.
34. Lee DH, Oh IY, Koo KT, Suk JM, Jung SW, Park JO, et al. Improvement in skin wrinkles using a preparation containing human growth factors and hyaluronic acid serum. Journal of Cosmetic and Laser Therapy. 2015; 17: 20-3.
35. Schouest JM, Luu TK, Moy RL. Improved texture and appearance of human facial skin after daily topical application of barley produced, synthetic, human-like epidermal growth factor (EGF) serum. Journal of drugs in dermatology: JDD. 2012; 11: 613-20.
36. Sachdev M, Chullikana A, Seetharam R, Shilpakar R, Sapna R, Velugotla K, et al. A Single Arm, Monocentric, Prospective, Open Label Study to Evaluate Anti-Ageing Efficacy of Human Growth Factors and Cytokines Containing Cosmetic Skin Serum in Indian Female Population. Journal of Cosmetics, Dermatological Sciences and Applications. 2017; 07: 118-32.
37. Ehrlich M, Rao J, Pabby A, Goldman MP. Improvement in the appearance of wrinkles with topical transforming growth factor beta (1) and l-ascorbic acid. Dermatologic surgery: official publication for American Society for Dermatologic Surgery [et al]. 2006; 32: 618-25.
38. Gold MH, Goldman MP, Biron J. Human growth factor and cytokine skin cream for facial skin rejuvenation as assessed by 3D in vivo optical skin imaging. Journal of drugs in dermatology: JDD. 2007; 6: 1018-23.
39. Gold MH, Goldman MP, Biron J. Efficacy of novel skin cream containing mixture of human growth factors and cytokines for skin rejuvenation. Journal of drugs in dermatology: JDD. 2007; 6: 197-201.
40. Lee YB, Lee KJ, Park HJ, Cho BK. Topical application of growth factors after carbon dioxide fractional laser therapy: a randomized controlled split-face study. Journal of cosmetic and laser therapy: official publication of the European Society for Laser Dermatology. 2011; 13: 38-40.
41. Zoumalan CI, Tadayon SC, Roostaeian J, Rossi AM, Gabriel A. Safety and Efficacy of a Scar Cream Consisting of Highly Selective Growth Factors Within a Silicone Cream Matrix: A Double-Blinded, Randomized, Multicenter Study. Aesthetic surgery journal. 2019; 39: 319-30.
42. McKnight B, Seidel R, Moy R. Topical Human Epidermal Growth Factor in the Treatment of Senile Purpura and the Prevention of Dermatoporosis. Journal of drugs in dermatology: JDD. 2015; 14: 1147-50.

43. Kalasho BD, Minokadeh A, Zhang-Nunes S, Zoumalan RA, Shemirani NL, Waldman AR, et al. Evaluating the Safety and Efficacy of a Topical Formulation Containing Epidermal Growth Factor, Tranexamic Acid, Vitamin C, Arbutin, Niacinamide and Other Ingredients as Hydroquinone 4% Alternatives to Improve Hyperpigmentation: A Prospective, Randomized, Controlled Split Face Study. Journal of cosmetic science. 2020; 71: 263-90.
44. Mehta RC, Smith SR, Grove GL, Ford RO, Canfield W, Donofrio LM, et al. Reduction in facial photodamage by a topical growth factor product. Journal of drugs in dermatology: JDD. 2008; 7: 864-71.
45. Watson RE, Long SP, Bowden JJ, Bastrilles JY, Barton SP, Griffiths CE. Repair of photoaged dermal matrix by topical application of a cosmetic 'antiageing' product. The British journal of dermatology. 2008; 158: 472-7.
46. Seidel R, Moy RL. Reduced appearance of under-eye bags with twice-daily application of epidermal growth factor (EGF) serum: a pilot study. Journal of drugs in dermatology: JDD. 2015; 14: 405-10.
47. Kong M, Hong SE. Topical use of recombinant human epidermal growth factor (EGF)-based cream to prevent radiation dermatitis in breast cancer patients: a single-blind randomized preliminary study. Asian Pacific journal of cancer prevention: APJCP. 2013; 14: 4859-64.
48. Prakoeswa CRS, Natallya FR, Harnindya D, Thohiroh A, Oktaviyanti RN, Pratiwi KD, et al. The efficacy of topical human amniotic membrane-mesenchymal stem cell-conditioned medium (hAMMSC-CM) and a mixture of topical hAMMSC-CM + vitamin C and hAMMSC-CM + vitamin E on chronic plantar ulcers in leprosy:a randomized control trial. J Dermatolog Treat. 2018; 29: 835-40.
49. Tuyet HL, Nguyen Quynh TT, Vo Hoang Minh H, Thi Bich DN, Do Dinh T, Le Tan D, et al. The efficacy and safety of epidermal growth factor in treatment of diabetic foot ulcers: the preliminary results. International wound journal. 2009; 6: 159-66.
50. Hanft JR, Pollak RA, Barbul A, van Gils C, Kwon PS, Gray SM, et al. Phase I trial on the safety of topical rhVEGF on chronic neuropathic diabetic foot ulcers. Journal of wound care. 2008; 17: 30-2, 4-7.
51. Barone F, Bashey S, Woodin Jr FW. Clinical Evidence of Dermal and Epidermal Restructuring from a Biologically Active Growth Factor Serum for Skin Rejuvenation. Journal of drugs in dermatology: JDD. 2019; 18: 290-5.
52. Fu X, Shen Z, Chen Y, Xie J, Guo Z, Zhang M, et al. Randomised placebo-controlled trial of use of topical recombinant bovine basic fibroblast growth factor for second-degree burns. Lancet (London, England). 1998; 352: 1661-4.
53. Alhaddad M, Boen M, Wu DC, Goldman MP. Red Deer Umbilical Cord Lining Mesenchymal Stem Cell Extract Cream for Rejuvenation of the Face. Journal of drugs in dermatology: JDD. 2019; 18: 363-6.