Intracellular delivery of adenosine triphosphate enhanced healing process in full-thickness skin wounds in diabetic rabbits



      Small unilamellar lipid vesicles were used to encapsulate adenosine triphosphate (ATP-vesicles) for intracellular energy delivery and were tested for diabetic skin wounds in rabbits.


      Diabetes was induced by alloxan. The mean peak blood glucose concentration was 505 mg/dL. One ear was made ischemic and 80 full-thickness wounds were created in 10 animals. ATP-vesicles or saline was used and healing was compared.


      On the non-ischemic ears, mean closure time for ATP-vesicles–treated wounds was 13.7 days versus 16.4 days for saline-treated wounds (P < .05). On the ischemic ears, mean closure time for ATP-vesicles–treated wounds was 15.3 days versus 19.3 days for saline-treated wounds (P < .01). Histological study indicated better healing and re-epithelialization in the ATP-vesicles–treated wounds.


      Intracellular delivery of ATP accelerated the healing process of diabetic skin wounds on ischemic and non-ischemic rabbit ears. The mechanisms deserve further study but may be related to improved cellular energy supplies.


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        • Apelqvist J.
        • Bakker K.
        • van Houtum W.H.
        • et al.
        The development of global consensus guidelines on the management of the diabetic foot.
        Diabetes Metab Res Rev. 2008; 24: S116-S118
        • Diabetes Statistics. American Diabetes Association
        • Wild S.
        • Roglic G.
        • Green A.
        • et al.
        Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.
        Diabetes Care. 2004; 27: 1047-1053
        • Cohen I.K.
        • Diegelmenn R.F.
        • Yager D.R.
        • et al.
        Wound care and wound healing.
        in: Seymour I.S. Shires G.T. Spencer F.C. Principles of Sugery. McGraw-Hill, New York1999: 263-295
        • Greenhalgh D.G.
        Wound healing and diabetes mellitus.
        Clin Plast Surg. 2003; 30: 37-45
        • Blakytny R.
        • Jude E.
        The molecular biology of chronic wounds and delayed healing in diabetes.
        Diabet Med. 2006; 23: 594-608
        • Young M.J.
        Foot problem in diabetes.
        in: Pickup J.C. Textbook of Diabetes. Blackwell Science, Malden, MA2003: 1-57 (GW)
        • Im M.J.
        • Hoopes J.E.
        Energy metabolism in healing skin wounds.
        J Surg Res. 1970; 10: 459-464
        • Wang D.J.
        • Huang N.N.
        • Heppel L.A.
        Extracellular ATP shows synergistic enhancement of DNA synthesis when combined with agents that are active in wound healing or as neurotransmitters.
        Biochem Biophys Res Commun. 1990; 166: 251-258
        • Wang J.
        • Zhang Q.
        • Wan R.
        • et al.
        Intracellular ATP delivery enhanced skin wound healing in rabbits.
        Ann Plast Surg. 2009; 62: 180-186
      1. Chien S. Intracellular ATP delivery using highly fusogenic liposomes. Methods Mol Biol (In press).

        • Chiang B.
        • Essick E.
        • Ehringer W.
        • et al.
        Enhancing skin wound healing by direct delivery of intracellular adenosine triphosphate.
        Am J Surg. 2007; 193: 213-218
        • Chien S.
        Ischemic rabbit ear model created by minimally invasive surgery.
        Wound Repair Regen. 2007; 15: 928-935
        • Smith D.G.
        • Mills W.J.
        • Steen R.G.
        • et al.
        Levels of high energy phosphate in the dorsal skin of the foot in normal and diabetic adults: the role of 31P magnetic resonance spectroscopy and direct quantification with high pressure liquid chromatography.
        Foot and Ankle International/American Orthopaedic Foot and Ankle Society [and] Swiss Foot and Ankle Society. 1999; 20: 258-262
        • Ragazzi E.
        • Costa C.V.
        • Caparrotta L.
        • et al.
        Enzyme activities along the tryptophan-nicotinic acid pathway in alloxan diabetic rabbits.
        Biochim Biophys Acta. 2002; 1571: 9-17
        • Kloeters O.
        • Tandara A.
        • Mustoe T.
        Hypertrophic scar model in the rabbit ear: a reproducible model for studying scar tissue behavior with new observations on silicone gel sheeting for scar reduction.
        Wound Repair Regen. 2007; 15: S40-S45
        • Saulis A.S.
        • Mogford J.H.
        • Mustoe T.A.
        Effect of Mederma on hypertrophic scarring in the rabbit ear model.
        Plast Reconstr Surg. 2002; 110: 177-183
        • Greene D.
        Diabetic neuropathy: scope of the syndrome.
        Am J Med. 1999; 107: 2S-8S
        • Dinh T.
        • Veves A.
        Microcirculation of the diabetic foot.
        Curr Pharm Des. 2005; 11: 2301-2309
        • Brem H.
        • Tomic-Canic M.
        Cellular and molecular basis of wound healing in diabetes.
        J Clin Invest. 2007; 117: 1219-1222
        • Schaffer M.
        • Witte M.
        • Becker H.D.
        Models to study ischemia in chronic wounds.
        Int J Low Extremity Wounds. 2002; 1: 104-111
        • Fine N.
        • Mustoe T.
        Wound Healing.
        Lippincott, Philadelphia2001 (69–86)
        • Hunt T.K.
        • Pai M.P.
        The effect of varying ambient oxygen tensions on wound metabolism and collagen synthesis.
        Surg Gynecol Obstet. 1972; 135: 561-567
        • Almskog B.A.
        • Haljamae H.
        • Hasselgren P.O.
        • et al.
        Local metabolic changes in skeletal muscle following high-energy missile injury.
        J Trauma. 1982; 22: 382-387
        • Hinchliffe R.J.
        • Valk G.D.
        • Apelqvist J.
        • et al.
        A systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes.
        Diabetes/Metab Res Rev. 2008; 24: S119-S144
        • Thackham J.A.
        • McElwain D.L.
        • Long R.J.
        The use of hyperbaric oxygen therapy to treat chronic wounds: a review.
        Wound Repair Regen. 2008; 16: 321-330
        • Niinikoski J.
        Hyperbaric oxygen therapy of diabetic foot ulcers, transcutaneous oxymetry in clinical decision making.
        Wound Repair Regen. 2003; 11: 458-461
        • Chien S.
        Metabolic management.
        in: Toledo-Pereyra L. Organ Procurement and Preservation for Transplantation. Landes Bioscience Springer, New York2008: 1-42
        • Ferreira M.C.
        • Tuma Jr, P.
        • Carvalho V.F.
        • et al.
        Complex wounds.
        Clin Sao Paulo Brazil. 2006; 61: 571-578
        • Harding K.G.
        • Morris H.L.
        • Patel G.K.
        Science, medicine and the future: healing chronic wounds.
        BMJ. 2002; 324: 160-163
        • Ahn S.T.
        • Mustoe T.A.
        Effects of ischemia on ulcer wound healing: a new model in the rabbit ear.
        Ann Plast Surg. 1990; 24: 17-23
        • Yancopoulos G.D.
        • Davis S.
        • Gale N.W.
        • et al.
        Vascular-specific growth factors and blood vessel formation.
        Nature. 2000; 407: 242-248
        • Mo Y.
        • Wan R.
        • Wang J.
        • et al.
        Intracellular ATP delivery accelerates skin wound healing through up-regulation cytokines and vascular endothelial growth factors expressions.
        Wound Rep Regul. 2009; 17: A11
        • Taegtmeyer H.
        Energy metabolism of the heart: from basic concepts to clinical applications.
        Curr Probl Cardiol. 1994; 19: 59-113
        • Delamaire M.
        • Maugendre D.
        • Moreno M.
        • et al.
        Impaired leukocyte functions in diabetic patients.
        Diabet Med. 1997; 14: 29-34
        • Lindblad W.J.
        Animal models in wound healing research: do we need more?.
        Wound Repair Regen. 2000; 8: 81-82
        • Rees D.A.
        • Alcolado J.C.
        Animal models of diabetes mellitus.
        Diabet Med. 2005; 22: 359-370