MV-ligase probes for visualization of apoptotic clearance
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AbstractDESCRIPTION (provided by applicant): The specific aim of this phase I proposal is to test our newly developed intracellular ATP delivery technique for abdominal wound dehiscence. More than 200,000 incisional hernia repairs are performed annually in the United States at a financial cost of nearly 2.5 billion dollars without considering the loss of productivity. Reoperation is risky with a higher recurrence rate. Despite many advances in the field of surgery and surgical technique, the formation of hernias following abdominal wall incisions continues to be a perplexing and prevalent problem. Very little emphasis has been placed on prevention despite its obvious importance and the incidence has not been changed over 50 years. The formations of incisional hernias are multifactorial, but the exact mechanism is still unknown. Two major contributing factors are wound separation due to intrinsic and extrinsic factors and bacterial infection. These two factors may form a vicious cycle causing a final breakdown. If measures are taken to correct some of the contributing factors, hernia formation may be reduced or prevented-a stitch in time saves nine. Noveratech has developed a new technique for the delivery of Mg-ATP directly to the cytosol (ATP-vesicles or VitaSolTM).The technique has been tested in full-thickness excisional skin wounds in mice and rabbits. VitaSolTM healed wounds faster than all control dressings, which included Mg-ATP alone, lipid vesicles alone, a neutral cream, and the only FDA-approved prescription growth factor for wound care--Regranex. It generated granulation tissues within 24 hours. In incisional skin wounds, VitaSolTM produced wound tissues with much higher tensile strengths, breaking strengths, and stress/strain ratios. The most striking finding was an extremely early stem cell and macrophage accumulation accompanied by massive collagen production-a phenomenon never seen or reported in the past with any other treatment modalities. Although mechanistic study is not the aim of the current proposal, this technique operates via at least three pathways: 1) massive stem/progenitor cell trafficking and leukocyte chemotaxis caused by purinergic receptor activation; 2) improved cell survival and function by intracellularly delivered energy, which is especially important for neutrophils, lymphocytes, and macrophages to exert their bacteriocidal function; and 3) enhanced collagen production by activated macrophages resulting in reduced tissue separation, exudation, and infection. In this phase I study, weplan to expand our preliminary findings to compare VitaSolTM with its individual components in incisional wounds and to test its effects on abdominal fascial healing to prevent herniation. The project will fill a major gap in current surgical wound management. Noveratech plans to commercialize the product after proven effective in animal and human tests. The success of this product will benefit millions of patients who undergo abdominal surgery each year. The usage of this technique may be expanded to other surgical repair procedures and acute wounds. The potential impact is high. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: More than 200,000 incisional hernia repairs are performed annually in the United States and these repairs have very high failure rate. The formation of hernias following abdominal wall incisions continues to be a perplexing and prevalent problem. Very little emphasis has been placed on prevention despite its obvious importance and the incidence remains unchanged over 50 years. We have developed a new technique for intracellular energy delivery and have found its ability to enhance healing process. This is achieved by very early stem cell and macrophage trafficking and proliferation accompanied by massive direct collagen production by macrophages. In this phase I proposal, we will expand the usage of the technique to include skin and fascial incisions to further confirm the results. The success of this project will benefit millions of patients with abdominal surgery each yearand can be used in other medical conditions. The potential impact is high.
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