A new technique for diabetic foot ulcers

 描述(由申请人提供)：本提案是对新的NIDDK公告(PA-14-058)的响应，该公告呼吁开发针对1型糖尿病(T1D)并发症的新诊断、监测和治疗技术。据估计，在美国2580万糖尿病患者中，有15%-25%的人会在一生中的某个时候患上糖尿病足溃疡(DFU)。目前，即使是最好的治疗方法对这些伤口的治愈率也只有50%，而且这种愈合往往只是暂时的，复发的可能性很高。尽管慢性创面无法愈合的原因是多方面的，但一个关键的病理生理学因素是缺血--血液供应不足。缺血可能不是DFU的始动因素，因为大多数溃疡起源于神经病变、压力负荷和/或创伤。然而，组织缺血是阻碍愈合的主要原因--伤口不会在不出血的组织中愈合，而它们总是在大量出血的组织中愈合。缺血最严重的后果是细胞能量供应减少，因为从蛋白质合成到细胞迁移、增殖和功能的伤口愈合过程的每一个方面都需要能量。我们公司已经开发出一种技术，将镁-三磷酸腺苷包裹在非常小的单层脂泡中，用于细胞内递送(三磷酸腺苷-囊泡或VitaSolTM)。当我们在动物创伤模型中使用这项新技术时，不仅促进了愈合，而且产生了前所未有的结果：肉芽组织在不到24小时内开始出现。它会继续生长，并在3-5天内覆盖整个伤口。大量的细胞积聚和增殖不仅发生在创面壁上，而且还发生在没有血液供应的创腔内。我们从未在人类或任何其他陆地动物身上看到过这种现象，也没有通过任何其他治疗策略在文献中报道过这种现象。这种影响在长期(12个月或更长时间)糖尿病加缺血创面中似乎更加明显。虽然肉芽组织生长迅速，但表现出自我限制的特征，即使在2年后也没有增生性瘢痕形成或任何其他过度生长。像许多其他伤口护理专家一样，当我们第一次看到这个史无前例的结果时，我们不相信它，因为它看起来太好了，以至于不像是真的。然而，这种新的愈合反应已经在130多只兔子(1040多个伤口)中得到证实。在这个第一阶段的提案中，我们将在没有皮肤收缩的糖尿病伤口模型中比较VitaSolTM和Regranex，Regranex是FDA批准的唯一用于伤口护理的处方药生长因子，并进行初步的毒性研究。这两个目标的实现将使该项目离IND应用更近一步。我们的细胞内能量传递技术一直被认为是创新的。如果成功，它将为DFU的治疗提供一种廉价且易于使用的敷料，尽管开发或提出了数千种敷料，但仍未实现这一点。潜在的影响很大。

 DESCRIPTION (provided by applicant): 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.