Management of bioburden and tissue regeneration in diabetic wounds using engineered matrices

第一阶段SBIR提案的目标是证明一个固有的广泛的可行性- 广谱抗微生物组织支架基质，能够清除感染的细菌病原体， 并改善糖尿病患者的伤口愈合。延迟不愈合的糖尿病伤口是负责约 美国每年有10万例非创伤性下肢截肢。微生物感染进一步使 已经表明病原性生物膜在预防伤口中起主要作用 治愈生物膜的存在和多重耐药生物体（MDRO）的出现使得 目前的局部和全身抗生素对抗糖尿病伤口的效果越来越差 感染.虽然预防和消除糖尿病伤口的病原体是至关重要的，但同样重要的是， 重要的是通过组织再生促进伤口闭合以减少进一步伤口的机会 感染 不幸的是，目前的产品在这些方面都显示出有限的功效。G4 db，申报产品 通过（i）通过独特的作用机制预防/消除感染， 其是广谱抗菌的，和（ii）通过提供细胞附着位点来促进组织再生 在支架矩阵中。与目前临床使用的任何产品不同，G4 db不依赖于 使用任何外部添加的抗生素，而是利用电荷组成来发挥毒性 针对革兰氏阳性和阴性细菌（包括抗生素耐药菌株）。此外，G4 db依赖于 仅对序列的抗菌电荷比，因此是细胞友好的，非炎症性和无毒的 具有与天然细胞外基质（ECM）非常相似的结构和孔径。 为了确定治疗糖尿病伤口感染的可行性，我们提出了以下两项主要任务： 具体目的1）G4 db消除感染的体内治疗功效。证明体内 G4 db作为一种抗微生物剂预防铜绿假单胞菌（一种常见病原体）定植的可行性 与伤口感染有关。 2）G4 db组织支架基质促进组织再生。体内演示 G4 db作为组织支架基质促进全层背部组织再生的功效 糖尿病猪模型中的切除伤口。 预计生成的数据将提供必要的信息，以便将申报产品转移到 商业化在SBIR II期，我们将在感染伤口愈合猪模型中验证水凝胶， 建立GMP生产，并执行GLP研究，为我们的FDA申报做准备。

The goal of this Phase I SBIR proposal is to demonstrate the feasibility of an inherently broad- spectrum antimicrobial tissue scaffolding matrix capable of eliminating infecting bacterial pathogens, and improve wound closure in diabetics. Delayed non-healing diabetic wound is responsible for about 100,000 annual non-traumatic lower-limb amputations in the US. Microbial infections further complicate the wound and it has been suggested that pathogenic biofilms play a major role in the prevention of wound healing. The presence of biofilms and the emergence of multi drug resistant organisms (MDROs) have made the current topical and systemic antibiotics becoming progressively less effective to combat diabetic wound infections. While prevention and elimination of pathogens from a diabetic wound is crucial, it is equally important to promote the wound closure by tissue regeneration to reduce the chance of further wound infection. Unfortunately, current products all show limited efficacy in these aspects. G4db, the proposed product overcomes current limitations by both (i) preventing/eliminating infection through a unique mechanism of action that is broad spectrum antibacterial, and (ii) promoting tissue regeneration by providing cell attachment sites within the scaffolding matrix. Unlike any of the products currently used in the clinics, G4db does not rely on using any externally added antibiotics, but rather takes advantage of charge composition to exert toxicity against Gram-positive and -negative bacteria (including antibiotic resistant strains). Furthermore, G4db relies only on sequences for antimicrobial charge ratio, and therefore is cell friendly, non-inflammatory and nontoxic with a structure and pore size very similar to the native extracellular matrix (ECM). To establish feasibility for the treatment of diabetic wound infections, we propose the following two main tasks: Specific Aim 1) Therapeutic in vivo efficacy of G4db to eliminate infection. Demonstrate the in vivo feasibility of G4db as an antimicrobial that prevents colonization of P. aeruginosa, a common pathogen associated with wound infections. Specific Aim 2) G4db tissue scaffolding matrix accelerates tissue regeneration. Demonstrate in vivo efficacy of G4db as tissue scaffolding matrix that promotes tissue regeneration in full-thickness dorsal excisional wounds in a diabetic swine model. It is expected that the generated data will provide the necessary information to move the proposed product into commercialization. In SBIR Phase II, we will validate the hydrogel in an infected wound healing swine model, establish GMP manufacturing, and execute GLP studies in preparation for our FDA submission.