Wound Healing & Skin Repair Using Copper Peptides


 US Patents describing methods using GHK-Cu stimulating wound healing of wound and methods for enhancing wound healing through an animalUS Patent 4,665,054   New glycyl-L-histidyl-L-lysine copper derivatives of improved resistance to proteolytic enzymes and better fat solubility for use in inhibiting thromboxane production and enhancing wound healing.  Pickart  US Patent 4,760,051   Compositions containing glycyl-1-histidyl-1-lysine copper(II) enhance the wound healing process without evoking an antigenic response Pickart  US Patent 4,810,693   Copper glycyl-L-histidyl-L-lysine complexes enhance the healing of wounds and sores.  Pickart US Patent 4,877,770   New glycyl-histidyl-lysine ester copper complex compounds with anti-inflammatory and superoxide dismutase activity useful for enhancing wound healing
Pickart US Patent 4,937,230   Method for healing wounds in horses using a copper complex of Glycyl-L-Histidyl-L-lysine or derivatives on the affected area.  Pickart  US Patent 5,164,367   Compositions for accelerating wound healing in mammals containing cupric salt or complexes with amino acid or peptide
Wound healing in rats

The healing of surgical wound in 10 control rats and 10 GHK-Cu treated rats was investigated.

The application of GHK-Cu markedly stimulated wound closure

Acceleration of wound healing using glycyl-histidyl-lysine copper (II) Downey, Larrabee, Voci and Pickart (Virginia Mason Research Center) Surg. Forum 573-575, 1985
Healing of rat wounds  Chemoattraction of capillary endothelial cellsAnti-oxidant actions GHK-Cu was tested on the healing of rat wounds, capillary cell chemoattraction, and superoxide dismutase-like activity. GHK-Cu accelerated the healing of rat wounds and acted as a chemoattractant for capillary endothelial cells at 10exp (-12) M. GHK-Cu also possesses significant superoxide dismutase-like activity.Gly-l-his-l-lys copper(II) - A human growth factor with superoxide dismutase-like and wound healing activities Pickart, Downey, Lovejoy and Weinstein (University of Washington) In: Superoxide and Superoxide Dismutase (Elsevier, 1986) pp.555-558
Wound healing and skin transplantation in miceGHK-Cu was tested by injection for improving the healing of surgical wounds and the take of skin grafts GHK-Cu accelerated the healing of surgical wound and improve the take of skin graftsIamin: A human growth factor with multiple wound healing properties Pickart  In: Biology of Copper Complexes Plenum Press 1987, pp.273-282
Healing of wounds in miceGHK-Cu was tested for improving the closure of surgical wounds GHK-Cu accelerated the healing of surgical wounds in miceBiological activity of human plasma copper-binding growth factor glycyl-L-histidyl-L-lysine. Pickart and Lovejoy  Methods Enzymol 1987;147:314-28 
Wound healing in pigsPig WoundsPeriphery of wound injected with 50 micrograms of GHK-Cu in 1% DMSO. Control wounds received 1% DMSO only. By 17 days post wounding, GHK-Cu accelerated healing and induced a "star" pattern of strong wound contraction.Pickart, 1984, Unpublished
Wound healing in pigs The healing of punch biopsies wound in pigs was determined GHK-Cu markedly stimulated wound healing and collagen synthesis. The effect is highly localized to the immediate skin area that is treatedCounts, D, Hill E, Turner-Beatty M, Grotewiel M, Fosha-Thomas S, Pickart L. Effect of lamin on full thickness wound healing. Fed Am Soc Exp Biol 1992; A1636
Paw healing in dogsTested GHK-Cu on paw healing in dogs. Tripeptide-copper complex  improved the healing of pad wounds in 12 mature English Pointers. Collagen production was significantly greater in treated pads. Healing was best with light bandaging. Wet bandages nullified the tripeptide-Cu effect.

Effect of locally injected medications on healing of pad wounds in dogs.  Swaim SF, Vaughn DM, Kincaid SA, Morrison NE, Murray SS, Woodhead MA, Hoffman C.E, Wright JC, Kammerman JR, College of Veterinary Medicine, Auburn University, AL, USA, Am J Vet Res 1996 Vol. 57, 394-9

Dog surgical wounds Effect of GHK-Cu and GHKF-Cu on wound healing of surgical wounds in dogs. GHK-Cu and GHKF-Cu increased wound closure and contraction and markedly increase the production of granulation tissue. 

Evaluation of multipeptide copper complex medications on open wound healing in dogs.  Swaim, Bradley, Spano, McGuire and Hoffman  (College of Veterinary Medicine, Auburn University, AL, USA)  J Amer Ani Hos Assoc. 29, 519-525, 1993

Human - Refractory Venous Stasis Ulcers and Diabetic UlcersEffect of GHK-Cu non-ionic cream with minimal preservative was tested on 60 patients GHK-Cu cream accelerated wound re-epithelializationEffects of the tripeptide glycyl-l-histidyl-l-lysine copper(II) on healing. Clinical and biochemical correlations.  Aupaix, Maquart, Salagnac, Pickart, Gillery, Borel and Kalis J Invest Derm 94:390, 1990
Human - Acute Surgical WoundsTested GHK-Cu cream with benzoyl alcohol as preservative on healing after Moh's surgery. GHK-Cu increased wound healing and skin re-epithelializationFish S, Katz I, Hien NR, Briden ME, Johnson JA, Patt, L, Evaluation of glycyl-1-histidyl-1-lysine copper complex in acute wound healing. Wounds 1991, 3:171-177;
Healing in immune suppressed rats

Healing is very impaired in immune suppressed patients and wound contraction is impaired -  Rats were immune suppressed with cortisone injections then the effect of GHK-Cu determined.

In immune suppressed rats, collagen synthesis was 23% of that in normal rats. GHK-Cu more than tripled collagen synthesis in these rats, raising it to 77% of normal and restored normal healing.  GHK-Cu restored normal wound contraction in suppressed rats

Stimulation of skin healing in immunosuppressed rats  H. P. Ehrlich (Harvard Medical School, Boston, USA)  Presented at Symposium on collagen and skin repair Reims, France  Sept. 12-13 1991
Human - Diabetic skin ulcers

Tested GHK-Cu cream on healing of skin ulcers.

GHK-Cu increased ulcer re-epithelialization

Massey P, Patt L, D'Aoust JC, The effects of glycyl-l-histidyl-l-lysine copper chelate on the healing of diabetic ulcers, Wounds 4:21-28, 1992
Human -  Diabetic skin ulcersTested GHK-Cu cream on healing of skin ulcers GHK-Cu increased skin  ulcer re-epithelialization

Enhanced healing of ulcers in patients with diabetes by topical treatment of glycyl-l-histidyl-l-lysine  Mulder GD, Patt L, Sanders L, Rosenstock J, Altman MI, Hanley ME, Duncan GW,  Wound Rep Reg 2:259-269, 1994


Tested GHK-Cu on the healing of linear incision wounds.

GHK-Cu increased wound tensile strength by 74% and neovascularity by 69%.

The combined effects of glycyl-l-histidyl-l-lysine copper (II) and Cell-Tak on the healing of linear incision wounds.  Schmidt SP, Resser JR, Sims RL, Mullins DL and Smith DJ   (University of Akron, Ohio, USA)  Wounds 6, 62-67, 1994
Wound healing and fibroblast production of collagen in guinea pigsThe effects of GHK-Cu and three synthetic analogues on wound healing of the guinea pig dorsal skin, as well as on cultured fibroblasts, were examined. Hydroxyproline, proteins, DNA and semicarbazide- sensitive amine oxidase, with a high affinity for benzylamine, were measured, and the histology of the wounds was observed after staining with hematoxylin/eosin.GHK-Cu and the analogues caused a decrease of the activity of semicarbazide sensitive amine oxidase, with a high affinity for benzylamine, 4-8 days after surgery, followed by an increase on day 11 that was higher than in the control group. A slower reorganization of the skin and a delayed activation of fibroblasts are  observed with these peptides-Cu complexes. The peptides had a direct effect on fibroblasts. The products at a concentration of 10exp (-7) M, decreased cell reproduction and increased collagen expression.Effect of tripeptide-copper complexes on the process of skin wound healing and on cultured fibroblasts. Buffoni, Pino and Dal Pozzo (Department of Pharmacology, University of Florence, Firenze, Italy) Arch Int Pharmacodyn Ther 1995 330(3):345-60
MiceThe use of breakdown resistant copper peptides to stimulate skin repair and wound healing US Patent 5,382,431   Tissue protective and regenerative compositions  Pickart 
Human skin repair

Tested 2nd generation SRCPs on repair of human nickel allergy injured skin.

Placebo-controlled double-blinded study found an accelerated the recovery of skin after injury and plus potent anti-inflammatory action.

In vivo nickel contact dermatitis: human model for topical therapeutics. Zhai, Chang, Singh, and Maibach  (University of California, San Francisco, USA) Contact Dermatitis Vol. 40, pp. 205-208, 1999
Human skin repair

Tested 2nd generation SRCPs on repair human tape stripped damaged skin.

Placebo-controlled double-blinded study found an accelerated the rate of skin repair

Stripped skin model to predict irritation potential of topical agents in vivo in man.  Zhai, Poblete, and Maibach  (University of California, San Francisco, USA)  International Journal of Dermatology, Volume 37, pages 386-389, 1998
Human skin repair

Tested 2nd generation SRCPs on repair of human 24-hour detergent damaged skin.

Placebo-controlled double-blinded study found accelerated the rate of skin repair

Sodium lauryl sulfate damaged skin in vivo in man: a water barrier repair model. Zhai, Leow, and Maibach  (University of California, San Francisco, USA) Skin Research and Technology, Volume 4,  pages 24-27, 1998
Human skin repair

Tested 2nd generation SRCPs on repair of human  acetone damaged skin.

Placebo-controlled double-blinded study found an accelerated the rate of skin repair

Human barrier recovery after acute acetone perturbation: an irritant dermatitis model.  Zhai, Leow, and Maibach (University of California, San Francisco, USA)  Clinical and Experimental Dermatology, Volume 23, pages 11-13, 1998
Effect of GHK-Cu on healing of ischemic open wounds in rats.GHK-Cu caused a significant decrease in wound area (64.5% GHK-Cu vs 28.2% control) by day 13. GHK-Cu also significantly lowered concentrations of TNF-alpha and MMP-2 and MMP-9.Canapp SO Jr, Farese JP, Schultz GS, Gowda S, Ishak A.M, Swaim SF, Vangilder J, Lee-Ambrose L, Martin FG, The effect of topical tripeptide-copper complex on healing of ischemic open wounds, Vet Surg. 2003 Nov-Dec;32(6):515-23
Rat dermal skin repairBiotin was attached to GHK then bound to collagen films. This gave increased wound contraction, increased cell proliferation, and produced a high expression of the antioxidant superoxide dismutase. Tissue copper levels were increased 9-fold.Arul V, Gopinath D, Gomathi K, Jayakumar R. Biotinylated GHK peptide incorporated collagenous matrix: A novel biomaterial for dermal wound healing in rats. Biomed Mater Res B Appl Biomater. 2005 May;73(2):383-91
Compare GHK-Cu and zinc oxide creams for wound healingThe unhealed wound area was smaller and wound contraction was higher in the GHK-Cu than in the zinc oxide group and the control. Median time for the coverage of the wound bed with granulation tissue was significantly shorter in the GHK-Cu group than in the other groups. Filling of the open wound with granulation tissue to skin level was significantly slower in the control group than in the other two groups. Neovascularization was best observed in the GHK-Cu group. The authors suggest that GHK-Cu is a better choice in the treatment protocols of open wounds than zinc oxide.

Cangul IT, Gul NY, Topal A, Yilmaz R, Evaluation of the effects of topical tripeptide-copper complex and zinc oxide on open-wound healing in rabbits. Vet Dermatol. 2006 Dec;17(6):417-23.

Biotinylated GHK peptide (BioGHK) incorporated collagen biomaterial (PIC) was tested for wound healing in diabetic rats.In diabetic rats treated with BioGHK collagen, healing was hastened with an increased rate of wound contraction. Glutathione (GSH) and ascorbic acid levels in the skin of streptozotocin-induced diabetic rats were higher in the PIC group as compared to control (Untreated) and collagen (Collagen Film--CF) treated groups. Superoxide dismutase (SOD) and catalase (CAT) activity was altered in all the groups. Fibroblast cell culture studies suggest that PIC promotes fibroblast growth, revealed epithelialization, increased synthesis of collagen and activation of fibroblasts and mast cells in the PIC group. BioGHK incorporated collagen may be an approach to enhance diabetic wound healing.

Arul V, Kartha R, Jayakumar R, A therapeutic approach for diabetic wound healing using biotinylated GHK incorporated collagen matrices, Life Sci. 2007 Jan 2;80(4):275-84.

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