REDUCING LAPAROTOMY WOUND FAILURE

描述(由申请人提供)：这一第一阶段提案的具体目标是测试我们新开发的用于腹部伤口裂开的细胞内ATP输送技术。在美国，如果不考虑生产力的损失，每年需要花费近25亿美元进行超过20万例的腹股沟修补手术。再次手术风险较大，复发率较高。尽管在外科领域和外科技术方面取得了许多进步，但腹壁切开后腹股沟的形成仍然是一个令人困惑和普遍的问题。尽管预防显然很重要，但对预防的重视很少，而且50年来发病率没有改变。切口疝气的形成是多因素的，但确切的机制仍不清楚。两个主要的致病因素是内因和外因造成的伤口分离和细菌感染。这两个因素可能会形成恶性循环，导致最终的崩溃。如果采取措施纠正一些致病因素，可能会减少或预防腹股沟的形成--及时缝一针可以省去九针。Noveratech已经开发出一种将镁-三磷酸腺苷直接输送到胞浆中的新技术(三磷酸腺苷-囊泡或VitaSolTM)。这项技术已经在小鼠和兔子的全层切除皮肤伤口上进行了测试。VitaSolTM的伤口愈合速度比所有对照敷料都要快，这些敷料包括单独的镁-三磷酸腺苷、单独的脂泡、中性面霜和FDA批准的唯一用于伤口护理的处方生长因子--Regranex。它在24小时内产生了肉芽组织。在伤口皮肤伤口中，VitaSolTM生产的伤口组织具有更高的抗张强度、断裂强度和应力/应变比。最引人注目的发现是干细胞和巨噬细胞极早期聚集，伴随着大量胶原蛋白的产生--这一现象在过去任何其他治疗方式中从未见过或报道过。虽然机制研究不是当前建议的目的，但这项技术至少通过三条途径进行：1)由嘌呤能受体激活引起的大量干/祖细胞运输和白细胞趋化；2)通过细胞内传递的能量改善细胞存活和功能，这对中性粒细胞、淋巴细胞和巨噬细胞发挥杀菌功能特别重要；以及3)通过激活的巨噬细胞增加胶原的产生，从而减少组织分离、渗出和感染。在这一阶段的研究中，我们计划扩大我们的初步发现，将VitaSolTM与其在伤口中的单独成分进行比较，并测试其对腹筋膜愈合的影响，以防止腹股沟突出。该项目将 填补了目前外科伤口管理中的一个主要空白。Noveratech计划在动物和人体试验中证明有效后，将该产品商业化。该产品的成功将使每年接受腹部手术的数百万患者受益。这项技术的使用可能会扩展到其他外科修复程序和急性伤口。潜在的影响很大。

DESCRIPTION (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, we plan 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.