REDUCING LAPAROTOMY WOUND FAILURE

描述（由申请人提供）：本I期提案的具体目的是测试我们新开发的用于腹部伤口裂开的细胞内ATP递送技术。在美国，每年进行超过20万例切口疝修补术，在不考虑生产力损失的情况下，财务成本接近25亿美元。再次手术风险大，复发率高。尽管在外科手术和外科技术领域取得了许多进展，但腹壁切口后疝的形成仍然是一个令人困惑和普遍的问题。尽管预防的重要性显而易见，但对预防的重视程度却很低，而且50年来发病率没有改变。切口疝的形成是多因素的，但确切的机制仍不清楚。两个主要的影响因素是由于内在和外在因素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，最终导致崩溃。如果采取措施来纠正一些促成因素，疝的形成可能会减少或预防及时一针节省九针。Noveratech开发了一种新技术，用于将Mg-ATP直接递送到胞质溶胶（ATP囊泡或VitaSolTM）。该技术已在小鼠和兔子的全层切除皮肤伤口中进行了测试。VitaSolTM伤口愈合速度快于所有对照敷料，其中包括单独的Mg-ATP，单独的脂质囊泡，中性乳膏和唯一FDA批准的伤口护理处方生长因子-Regranex。它在24小时内生成肉芽组织。在切口皮肤伤口中，VitaSolTM产生的伤口组织具有更高的拉伸强度、断裂强度和应力/应变比。最引人注目的发现是一个非常早期的干细胞和巨噬细胞的积累，伴随着大量的胶原蛋白的产生，这是一种在过去的任何其他治疗方式中从未见过或报道过的现象。尽管机制研究不是当前提议的目的，但该技术通过至少三个途径操作：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性; 2）通过细胞内递送能量改善细胞存活和功能，这对于中性粒细胞、淋巴细胞和巨噬细胞发挥其杀菌功能特别重要;和3）通过活化的巨噬细胞增强胶原蛋白的产生，导致减少的组织分离、渗出和感染。在这项I期研究中，我们计划扩大我们的初步研究结果，比较VitaSolTM及其单个成分在切口伤口中的作用，并测试其对腹部筋膜愈合的影响，以预防疝。该项目将 填补了当前外科伤口处理的主要空白。Noveratech计划在动物和人体试验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。该技术的使用可以扩展到其他外科修复手术和急性伤口。潜在影响很大。

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.