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

使用工程基质管理糖尿病伤口的生物负载和组织再生

• 批准号: 9347778
• 负责人: Manav Mehta
• 金额: $ 29.25万
• 依托单位: GEL4MED, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2021-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9347778
• 关键词: Address; Amino Acids; Amputation; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Arginine; Attention; Bacteria; Bacterial Drug Resistance; Binding; Biological; Caring; Cell-Matrix Junction; Cells; Cellular Infiltration; Characteristics; Charge; Clinic; Clinical; Code; Data; Debridement; Delaware; Deposition; Diabetes Mellitus; Diabetic Foot Ulcer; Diabetic ulcer; Diabetic wound; Dorsal; Engineering; Environment; Excision; Extracellular Matrix; Failure; Family suidae; Fiber; Gel; Goals; Health; Histopathology; Hospitals; Human; Hydrogels; In Vitro; Incidence; Infection; Infection prevention; Lead; Legal patent; Light; Local Anti-Infective Agents; Lower Extremity; Measurement; Membrane; Methods; Microbial Biofilms; Microscopic; Modality; Modeling; Multi-Drug Resistance; Natural regeneration; Oligopeptides; Optics; Organism; Pathogenicity; Patients; Peptide Hydrolases; Phase; Play; Polymers; Preparation; Prevention; Property; Pseudomonas aeruginosa; Recurrence; Resistance; Resort; Rights; Role; Shapes; Site; Skin Substitutes; Small Business Innovation Research Grant; Staphylococcus aureus; Sterile coverings; Structure; Surface; Technology; Testing; Therapeutic; Thick; Time; TimeLine; Topical application; Toxic effect; Ulcer; Universities; Work; Wound Healing; Wound Infection; animal tissue; antimicrobial; bacterial resistance; base; chronic wound; combat; commercialization; cost; diabetic; diabetic patient; disease transmission; healing; improved; in vivo; killings; limb amputation; microbial; mortality; multi-drug resistant pathogen; nanosized; pathogen; prevent; resistant strain; scaffold; synthetic tissue scaffolding; tissue regeneration; tissue support frame; treatment strategy; wound; wound closure

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.

第一阶段 SBIR 提案的目标是证明本质上广泛的可行性 能够消除感染性细菌病原体的光谱抗菌组织支架基质， 并改善糖尿病患者的伤口闭合。糖尿病伤口延迟不愈合是造成约 美国每年有 100,000 例非创伤性下肢截肢。微生物感染使病情进一步复杂化 伤口，有人认为致病性生物膜在预防伤口方面发挥着重要作用 康复。生物膜的存在和多重耐药微生物（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逐渐减弱 感染。虽然预防和消除糖尿病伤口中的病原体至关重要，但同样重要 通过组织再生促进伤口闭合以减少进一步伤口的机会很重要 感染。 不幸的是，目前的产品在这些方面都表现出有限的功效。 G4db，提议的产品 通过以下方式克服了当前的局限性：(i) 通过独特的作用机制预防/消除感染 它具有广谱抗菌性，并且 (ii) 通过提供细胞附着位点促进组织再生 在脚手架矩阵内。与目前诊所使用的任何产品不同，G4db 不依赖于 使用任何外部添加的抗生素，而是利用电荷成分来发挥毒性 对抗革兰氏阳性和阴性细菌（包括抗生素耐药菌株）。此外，G4db 依赖于 仅针对抗菌电荷比的序列，因此对细胞友好、非炎症且无毒 其结构和孔径与天然细胞外基质（ECM）非常相似。 为了确定治疗糖尿病伤口感染的可行性，我们提出以下两项主要任务： 具体目标 1) G4db消除感染的体内疗效。展示体内 G4db 作为抗菌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。 具体目标 2) G4db 组织支架基质加速组织再生。体内演示 G4db作为组织支架基质促进背侧全层组织再生的功效 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，以将拟议的产品转移到 商业化。在 SBIR 第二阶段，我们将在受感染的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 FDA 提交做准备。