This proposal is submitted in response to the new NIDDK announcement (PA-14- 058) calling for development of new diagnostic, monitoring, and therapeutics technologies for the complications of type 1 diabetes (T1D). An estimated 15-25% of the 25.8 million diabetic patients in this country will develop diabetic foot ulcers (DFU) at some point in their lives. Currently, even the best available treatments achieve only a 50% healing rate for these wounds-and this healing is often only temporary with a high chance of recurring. Although the causes of non-healing chronic wounds are multifactorial, one critical pathophysiology is ischemia-a deficient blood supply. Ischemia may not be the initiating factor for DFU, because most ulcers start from a combination of neuropathy, pressure loading, and/or trauma. However, tissue ischemia is the main cause that hinders healing-wounds do not heal in tissue that does not bleed, whereas they always heal in tissue that bleeds extensively. The most critical consequence of ischemia is a decreased cellular energy supply because energy is required in every aspect of the wound healing process from protein synthesis to cell migration, proliferation, and functioning. Our company has developed a technique to encapsulate Mg-ATP into very small unilamellar lipid vesicles for intracellular delivery (ATP-vesicles or VitaSolTM). When we use this new technique in animal wound models, not only healing is enhanced, but also produces an unprecedented result: Granulation tissue starts to appear in less than 24 hours. It continues to grow and covers the whole wound within 3-5 days. Massive cell accumulation and proliferation occur not only on the wound wall, but also in the wound cavity where no blood supply exists. We have never seen this phenomenon in humans or any other land animals, nor has it been reported in the literature by any other treatment strategy. The effect seems even more pronounced in long-term (12 months or longer) diabetic plus ischemic wounds. Although the granulation tissue growth is rapid, it shows a self-limiting feature, which results in no hypertrophic scar formation or any other overgrowth even after 2 years. Like many other wound care specialists, when we first saw this unprecedented result, we did not believe it because it seemed too good to be true. However, this novel healing response has been confirmed in more than 130 rabbits (over 1040 wounds). In this phase I proposal, we will compare VitaSolTM with Regranex, the only FDA- approved prescription growth factor for wound care, in a diabetic wound model without skin contraction, and perform a preliminary toxicity study. The accomplishment of these two goals will bring the project one step closer to IND application. Our technique of intracellular energy delivery has consistently been viewed as innovative. If successful, it will provide an inexpensive and easy to use dressing for DFU treatment, something not yet achieved despite thousands of dressings developed or proposed. The potential impact is high.
Public Health Relevance Statement: Public Health Relevance: Diabetic foot ulcer is a major and disabling complication but no effective treatment is currently available. We have developed an intracellular energy delivery technique for wound care. In animal tests, it causes granulation tissue to appear in less than 24 hours and covers wound cavity quickly. The effect is more prominent in long-term diabetic plus ischemic wounds. The elimination of the traditional lag time in wound healing process, and the ability to nourish massive cells in wound cavities devoid of blood supply are two features never achieved with any other treatments. This phase I project will compare the effectiveness of this new treatment with the only FDA-approved prescription growth factor for wound care--Regranex in diabetic wounds, and perform a preliminary toxicity tests in male and female rabbits. The success of this phase I project will pave the way for more extensive tests in phase II and prepare the technique for IND application. The final success will benefit the millions of diabetic patients with unmanageable chronic wounds, and will also have the potential to be applied to other areas of medicine where ischemia is involved.
Project Terms: Animal Testing; Animals; Area; Becaplermin; Calculi; Caring; Cell membrane; cell motility; Cell Proliferation; Cell Survival; Cells; Characteristics; Chronic; Clinical; compare effectiveness; Complication; Country; Development; diabetic; Diabetic Foot Ulcer; diabetic patient; Diabetic wound; Drug Controls; effective therapy; Encapsulated; Energy Supply; FDA approved; Female; Functional disorder; Goals; Granulation Tissue; Growth; Growth Factor; Healed; healing; Hemorrhage; Hemostatic function; Hour; Human; Hypertrophic Cicatrix; Inflammation; innovation; Insulin-Dependent Diabetes Mellitus; Ischemia; Lipids; Literature; macrophage; male; Medicine; Modeling; Monitor; National Institute of Diabetes and Digestive and Kidney Diseases; Neuropathy; non-diabetic; novel; novel diagnostics; One-Step dentin bonding system; Oryctolagus cuniculus; Phase; pressure; Process; Proliferating; Protein Biosynthesis; public health relevance; Reporting; response; Skin; Specialist; Sterile coverings; success; Supporting Cell; Techniques; Technology; Testing; Therapeutic; Time; tissue regeneration; Tissues; Toxic effect; Toxicity Tests; Trauma; treatment strategy; Ulcer; Use of New Techniques; Vascular blood supply; Vesicle; wound; Wound Healing
