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The effects of liposomal ATP on cutaneous wound healing
by Thomas, Candice Michelle, Ph.D., UNIVERSITY OF LOUISVILLE, 2007, 97 pages; 3286709
Abstract:
In chronic wounds such as diabetic foot ulcers and pressure ulcers, synthesis of adenosine triphosphate (ATP) is the rate limiting step in the wound healing process. Large wounds result in increased metabolic demand to produce the necessary factors for wound closure. However, the ischemia that accompanies these wounds compromises the oxygen supply/energy needed to maintain the viability of the wound border cells and controlled collagen production. As a result, in individuals with a compromised blood flow (e.g. diabetics), the healing process can take a longer time than acceptable. Our ATP/energy delivery system, liposomal-ATP composed of fusogenic lipid vesicles that encapsulate ATP allows copious amount of ATP to be delivered to the wound. We hypothesize that topical applications of liposomal encapsulated ATP will increase the rate of wound closure by increasing intracellular ATP of hypoxic fibroblasts.
Methods. Swine (70-80 lbs.) were inflicted with 10 full-thickness cutaneous wounds on their dorsal surface. The wounds were treated with 3 different forms of liposomal-ATP (aqueous, hydrogel, aerosolized) and compared to control wet wounds. Wound volume and area measurements (using the NIH imaging software) were quantified. At the completion of closure, full-thickness biopsies were taken for histological evaluation. In vitro experiments: human adult dermal fibroblasts were exposed to normal oxygen tension (20% O[SUB]2[/SUB]), low oxygen tension (2% O[SUB]2[/SUB]) and in culture media with low glucose and treated with liposomal-ATP, free ATP or HBSS. The cells were assessed for viability and intracellular ATP content via bioluminescence. Liposomal-ATP was characterized in terms of size and delivery capacity in fibroblasts.
Results. Wounds treated with aerosolized liposomal-ATP exhibited faster closure rates compared to control during the early stages of wound healing with early appearances of granulation tissue and thicker epidermis during the latter stages of healing. In vitro, 24 hours of hypoxia decreases intracellular ATP to 25% of normal levels. One hour incubation of liposomal-ATP + reoxygenation increased intracellular ATP to 70% of the normal level and beyond normal levels with 2 hours incubation. One hour incubation of liposomal-ATP + additional hypoxia increased intracellular ATP from 25% to 90% of normal level and dropped to 70% of normal levels with 2 hours incubation. Free ATP also mildly increased intracellular ATP, but liposomal-ATP provided much higher increases.
Conclusion. Delivery of exogenous ATP to increase ATP bioavailability in ischemic wounds resulted in improved closure rates. The results may be associated with increased intracellular ATP levels in hypoxic fibroblasts, but the precise mechanism behind this observation remains to be elucidated.
by Thomas, Candice Michelle, Ph.D., UNIVERSITY OF LOUISVILLE, 2007, 97 pages; 3286709
Abstract:
In chronic wounds such as diabetic foot ulcers and pressure ulcers, synthesis of adenosine triphosphate (ATP) is the rate limiting step in the wound healing process. Large wounds result in increased metabolic demand to produce the necessary factors for wound closure. However, the ischemia that accompanies these wounds compromises the oxygen supply/energy needed to maintain the viability of the wound border cells and controlled collagen production. As a result, in individuals with a compromised blood flow (e.g. diabetics), the healing process can take a longer time than acceptable. Our ATP/energy delivery system, liposomal-ATP composed of fusogenic lipid vesicles that encapsulate ATP allows copious amount of ATP to be delivered to the wound. We hypothesize that topical applications of liposomal encapsulated ATP will increase the rate of wound closure by increasing intracellular ATP of hypoxic fibroblasts.
Methods. Swine (70-80 lbs.) were inflicted with 10 full-thickness cutaneous wounds on their dorsal surface. The wounds were treated with 3 different forms of liposomal-ATP (aqueous, hydrogel, aerosolized) and compared to control wet wounds. Wound volume and area measurements (using the NIH imaging software) were quantified. At the completion of closure, full-thickness biopsies were taken for histological evaluation. In vitro experiments: human adult dermal fibroblasts were exposed to normal oxygen tension (20% O[SUB]2[/SUB]), low oxygen tension (2% O[SUB]2[/SUB]) and in culture media with low glucose and treated with liposomal-ATP, free ATP or HBSS. The cells were assessed for viability and intracellular ATP content via bioluminescence. Liposomal-ATP was characterized in terms of size and delivery capacity in fibroblasts.
Results. Wounds treated with aerosolized liposomal-ATP exhibited faster closure rates compared to control during the early stages of wound healing with early appearances of granulation tissue and thicker epidermis during the latter stages of healing. In vitro, 24 hours of hypoxia decreases intracellular ATP to 25% of normal levels. One hour incubation of liposomal-ATP + reoxygenation increased intracellular ATP to 70% of the normal level and beyond normal levels with 2 hours incubation. One hour incubation of liposomal-ATP + additional hypoxia increased intracellular ATP from 25% to 90% of normal level and dropped to 70% of normal levels with 2 hours incubation. Free ATP also mildly increased intracellular ATP, but liposomal-ATP provided much higher increases.
Conclusion. Delivery of exogenous ATP to increase ATP bioavailability in ischemic wounds resulted in improved closure rates. The results may be associated with increased intracellular ATP levels in hypoxic fibroblasts, but the precise mechanism behind this observation remains to be elucidated.