tions appear to be small and active, and this size and activity
have been seen to be synergistic and in line with good elastin
formation.29 In other words, large, mature adipocytes have
been associated with diminished elastin—manifesting as aged
sagging skin—whereas younger, smaller, newly synthesized
adipocytes are accompanied by increased elastin levels. PGC1a
stimulators are thus useful candidates for increasing adipogenesis,
providing small active adipocytes through this PPARγ
activation pathway.
DISCUSSION/CONCLUSION
Fillers and injection therapy are the most frequently performed aesthetic procedures. Inevitably, a certain amount of discomfort and more significantly occasional bruising is an undesired consequence of medical or cosmetic procedures to the face and body. Additionally, the introduction of synergistic volume replacement of collagen, elastin, hyaluronic acid, and fat, particularly at a more superficial extracellular matrix level serves as an excellent adjunct to the injection therapy. Active agents have been selected that have been demonstrated to improve the efficiency of macrophage phagocytosis of RBCs and heme using a unique in vitro model.
The plasminogen system is essential for dissolution of fibrin clots. Lactoferrin, an iron-binding milk glycoprotein, blocks plasminogen activation on the cell surface by direct binding to human plasminogen, decreasing conversion to plasmin (it is a plasmin inhibitor). It also has anti-microbial activity.3-5 Lactoferrin effects range from antimicrobial to anti-inflammatory and immune-modulator activities; however, its most striking physicochemical feature is its high iron-binding affinity.6 Only transferrin has the ability to retain this metal over a wide range of pH values. Thus, it is essential in the process of bruising resolution and in the prevention of post-inflammatory pigmentation. 6 It also induces phagocytosis of cells, microbes and debris.7 Phosphatidylserine (PS) resides on the inner cell membrane of red blood cells and induces phagocytosis of the RBCs.8 Tripeptide-1 and hexapeptide-12 in combination have been tested comprehensively in previous in vitro and human studies and have shown important synergistic benefits, particularly in the area of extracellular matrix recycling and neocollagenesis and neoelastogenesis.9 Hexapeptide-11 is a potent stimulator of autophagy and macrophage clustering.10
Volumetric advantages and efficacy of the actives have been previously demonstrated in clinical trials30 and this combination together with anti-inflammatory, anti-biofilm, bacteriostatic and anti-bruising actives create a comprehensive and unique topical adjunct to injection therapy. Validation of hastened bruising resolution has been achieved using in vitro and in vivo studies.
The plasminogen system is essential for dissolution of fibrin clots. Lactoferrin, an iron-binding milk glycoprotein, blocks plasminogen activation on the cell surface by direct binding to human plasminogen, decreasing conversion to plasmin (it is a plasmin inhibitor). It also has anti-microbial activity.3-5 Lactoferrin effects range from antimicrobial to anti-inflammatory and immune-modulator activities; however, its most striking physicochemical feature is its high iron-binding affinity.6 Only transferrin has the ability to retain this metal over a wide range of pH values. Thus, it is essential in the process of bruising resolution and in the prevention of post-inflammatory pigmentation. 6 It also induces phagocytosis of cells, microbes and debris.7 Phosphatidylserine (PS) resides on the inner cell membrane of red blood cells and induces phagocytosis of the RBCs.8 Tripeptide-1 and hexapeptide-12 in combination have been tested comprehensively in previous in vitro and human studies and have shown important synergistic benefits, particularly in the area of extracellular matrix recycling and neocollagenesis and neoelastogenesis.9 Hexapeptide-11 is a potent stimulator of autophagy and macrophage clustering.10
Volumetric advantages and efficacy of the actives have been previously demonstrated in clinical trials30 and this combination together with anti-inflammatory, anti-biofilm, bacteriostatic and anti-bruising actives create a comprehensive and unique topical adjunct to injection therapy. Validation of hastened bruising resolution has been achieved using in vitro and in vivo studies.
DISCLOSURES
Alan Widgerow is Chief Medical Office Alastin Skincare Inc.Michaela Bell is Director Clinical Research Alastin Skincare Inc.
John Garruto is consultant to Alastin Skincare Inc. Dr. Palm and
Dr. Jacob are consultants to Alastin Skincare Inc.
REFERENCES
1. Jeney V, Eaton JW, Balla G, Balla J. Natural history of the bruise: formation, elimination, and biological effects of oxidized hemoglobin. Oxidative med cell longev. 2013;2013:703571.
2. Sadeghpour M, Dover JS. Understanding delayed bruising after hyaluronic acid injections: why the molecule and not just the injection matters - letters and communications. Dermatol Surg. 2019;45(3):471-473.
3. Zwirzitz A, Reiter M, Skrabana R, et al. Lactoferrin is a natural inhibitor of plasminogen activation. J Biol Chem. 2018;293(22):8600-8613.
4. Ammons M, Ward L, James GA. Anti-biofilm efficacy of a lactoferrin/xylitol wound hydrogel used in combination with silver wound dressings. Int Wound J. 2011; 8:268-273.
5. Ammons MC, Copie V. Mini-review: Lactoferrin: a bioinspired, anti-biofilm therapeutic. Biofouling. 2013;29(4):443-455.
6. Sito G, Brancaccio G, Ledda C. A New Treatment of Dermal Filler Complications_ Liposomal Lactoferrin as Anti-Inflammatory, Anti-Edema and Antimicrobial Agent. www.societamedicinaestetica.it
7. GarcÃa-Montoya IA, Cendón TS, Arévalo-Gallegos S, Rascón-Cruz Q. Lactoferrin a multiple bioactive protein: An overview. Biochim. Biophys. Acta. 2012;1820(3):226-236.
8. Chang CF, Goods BA, Askenase MH, et al. Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage. J Clin Invest. 2018;128(2):607-624.
9. Widgerow AD, Fabi SG, Palestine RF, et al. Extracellular matrix modulation: optimizing skin care and rejuvenation procedures. J Drugs Dermatol. 2016;15(4s):S63-S71.
10. Widgerow A, Kilmer S, Garruto J, Stevens W. Non-surgical fat reduction and topical modulation of adipose tissue physiology. J Drugs Dermatol. 2019;18(4):375-380.
11. Xu Y, Ibrahim IM, Wosu CI, Ben-Amotz A, Harvey PJ. Potential of new isolates of dunaliella salina for natural beta-carotene production. Biology (Basel). 2018;7(1).
12. Marzotto M, Bonafini C, Olioso D, et al. Arnica montana stimulates extracellular matrix gene expression in a macrophage cell line differentiated to wound-healing phenotype. PloS one. 2016;11(11).
13. Kang JY, Tran KD, Seiff SR, Mack WP, Lee WW. Assessing the effectiveness of arnica montana and rhododendron tomentosum (ledum palustre) in the reduction of ecchymosis and edema after oculofacial surgery: preliminary results. Ophthalmic Plast Reconstr Surg. 2017;33(1):47-52.
14. Ashcroft G, Kielty C, Horan M, Ferguson M. Age-related changes in the temporal and spatial distributions of fibrillin and elastin mRNAs and proteins in acute cutaneous wounds of healthy humans. Am J Pathol. 1997; 183:80-89.
15. Cenizo V, Andre´ V, Reymermier C, Sommer P, Damour O, E. P. LOXL as a target to increase the elastin content in adult skin: a dill extract induces the LOXL gene expression. Exp Dermatol. 2006;15:574-581.
16. Noblesse E, Cenizo V, Bouez C, et al. Lysyl oxidase-like and lysyl oxidase are present in the dermis and epidermis of a skin equivalent and in human skin and are associated to elastic fibers. J Invest Dermatol. 2004;122(3):621-630.
17. Widgerow A. Topical skin restoration technology – advances in age management strategies. Modern Aesthetics. 2016(May/June):1-8. 18. Product monograph: UplevityTM. Lipotec. June 2013.
19. Ryu M, Nogami A, Kitakaze T, Harada N, Suzuki YA, Yamaji R. Lactoferrin induces tropoelastin expression by activating the lipoprotein receptor-related protein 1-mediated phosphatidylinositol 3-kinase/Akt pathway in human dermal fibroblasts. Cell Biol Int. 2017;41(12):1325-1334.
20. Ishii N, Kobayashi T, Matsumiya K, et al. Transdermal administration of lactoferrin with sophorolipid1This article is part of a Special Issue entitled Lactoferrin and has undergone the Journal's usual peer review process. Biochem Cell Biol. 2012;90(3):504-512.
21. Litwiniuk M, Krejner A, Grzela T. Hyaluronic acid in inflammation and tissue regeneration. wounds. 2016;28(3):78-88.
22. Product monograph: Symdecanox, Symrise June 2015.
23. Li H, Lee HS, Kim SH, Moon B, Lee C. Antioxidant and anti-inflammatory activities of methanol extracts of Tremella fuciformis and its major phenolic acids. J Food Sci. 2014;79(4):C460-468.
24. Liao WC, Hsueh CY, Chan CF. Antioxidative activity, moisture retention, film formation, and viscosity stability of Auricularia fuscosuccinea, white strain water extract. Biosci Biotechnol Biochem. 2014;78(6):1029-1036.
25. Saito S, Takayama Y, Mizumachi K, Suzuki C. Lactoferrin promotes hyaluronan synthesis in human dermal fibroblasts. Biotechnol Lett. 2011;33(1):33-39.
2. Sadeghpour M, Dover JS. Understanding delayed bruising after hyaluronic acid injections: why the molecule and not just the injection matters - letters and communications. Dermatol Surg. 2019;45(3):471-473.
3. Zwirzitz A, Reiter M, Skrabana R, et al. Lactoferrin is a natural inhibitor of plasminogen activation. J Biol Chem. 2018;293(22):8600-8613.
4. Ammons M, Ward L, James GA. Anti-biofilm efficacy of a lactoferrin/xylitol wound hydrogel used in combination with silver wound dressings. Int Wound J. 2011; 8:268-273.
5. Ammons MC, Copie V. Mini-review: Lactoferrin: a bioinspired, anti-biofilm therapeutic. Biofouling. 2013;29(4):443-455.
6. Sito G, Brancaccio G, Ledda C. A New Treatment of Dermal Filler Complications_ Liposomal Lactoferrin as Anti-Inflammatory, Anti-Edema and Antimicrobial Agent. www.societamedicinaestetica.it
7. GarcÃa-Montoya IA, Cendón TS, Arévalo-Gallegos S, Rascón-Cruz Q. Lactoferrin a multiple bioactive protein: An overview. Biochim. Biophys. Acta. 2012;1820(3):226-236.
8. Chang CF, Goods BA, Askenase MH, et al. Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage. J Clin Invest. 2018;128(2):607-624.
9. Widgerow AD, Fabi SG, Palestine RF, et al. Extracellular matrix modulation: optimizing skin care and rejuvenation procedures. J Drugs Dermatol. 2016;15(4s):S63-S71.
10. Widgerow A, Kilmer S, Garruto J, Stevens W. Non-surgical fat reduction and topical modulation of adipose tissue physiology. J Drugs Dermatol. 2019;18(4):375-380.
11. Xu Y, Ibrahim IM, Wosu CI, Ben-Amotz A, Harvey PJ. Potential of new isolates of dunaliella salina for natural beta-carotene production. Biology (Basel). 2018;7(1).
12. Marzotto M, Bonafini C, Olioso D, et al. Arnica montana stimulates extracellular matrix gene expression in a macrophage cell line differentiated to wound-healing phenotype. PloS one. 2016;11(11).
13. Kang JY, Tran KD, Seiff SR, Mack WP, Lee WW. Assessing the effectiveness of arnica montana and rhododendron tomentosum (ledum palustre) in the reduction of ecchymosis and edema after oculofacial surgery: preliminary results. Ophthalmic Plast Reconstr Surg. 2017;33(1):47-52.
14. Ashcroft G, Kielty C, Horan M, Ferguson M. Age-related changes in the temporal and spatial distributions of fibrillin and elastin mRNAs and proteins in acute cutaneous wounds of healthy humans. Am J Pathol. 1997; 183:80-89.
15. Cenizo V, Andre´ V, Reymermier C, Sommer P, Damour O, E. P. LOXL as a target to increase the elastin content in adult skin: a dill extract induces the LOXL gene expression. Exp Dermatol. 2006;15:574-581.
16. Noblesse E, Cenizo V, Bouez C, et al. Lysyl oxidase-like and lysyl oxidase are present in the dermis and epidermis of a skin equivalent and in human skin and are associated to elastic fibers. J Invest Dermatol. 2004;122(3):621-630.
17. Widgerow A. Topical skin restoration technology – advances in age management strategies. Modern Aesthetics. 2016(May/June):1-8. 18. Product monograph: UplevityTM. Lipotec. June 2013.
19. Ryu M, Nogami A, Kitakaze T, Harada N, Suzuki YA, Yamaji R. Lactoferrin induces tropoelastin expression by activating the lipoprotein receptor-related protein 1-mediated phosphatidylinositol 3-kinase/Akt pathway in human dermal fibroblasts. Cell Biol Int. 2017;41(12):1325-1334.
20. Ishii N, Kobayashi T, Matsumiya K, et al. Transdermal administration of lactoferrin with sophorolipid1This article is part of a Special Issue entitled Lactoferrin and has undergone the Journal's usual peer review process. Biochem Cell Biol. 2012;90(3):504-512.
21. Litwiniuk M, Krejner A, Grzela T. Hyaluronic acid in inflammation and tissue regeneration. wounds. 2016;28(3):78-88.
22. Product monograph: Symdecanox, Symrise June 2015.
23. Li H, Lee HS, Kim SH, Moon B, Lee C. Antioxidant and anti-inflammatory activities of methanol extracts of Tremella fuciformis and its major phenolic acids. J Food Sci. 2014;79(4):C460-468.
24. Liao WC, Hsueh CY, Chan CF. Antioxidative activity, moisture retention, film formation, and viscosity stability of Auricularia fuscosuccinea, white strain water extract. Biosci Biotechnol Biochem. 2014;78(6):1029-1036.
25. Saito S, Takayama Y, Mizumachi K, Suzuki C. Lactoferrin promotes hyaluronan synthesis in human dermal fibroblasts. Biotechnol Lett. 2011;33(1):33-39.
