Treatment of microbial keratitis and corneal wound healing

微生物性角膜炎的治疗和角膜伤口愈合

• 批准号: 10010777
• 负责人: Manav Mehta
• 金额: $ 38万
• 依托单位: GEL4MED, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010777
• 关键词: Affect; Animal Model; Anti-Bacterial Agents; Antibiotics; Antimicrobial Resistance; Artificial Tears; Autologous; Bacteria; Bacterial Eye Infections; Bacterial conjunctivitis; Bandage; Blindness; Cell Proliferation; Cell-Matrix Junction; Cicatrix; Clinical; Complex; Contact Lenses; Cornea; Corneal Injury; Corneal Neovascularization; Defect; Development; Dyes; Edema; Endophthalmitis; Epithelial; Epithelial Cells; Epithelium; Exhibits; Extracellular Matrix; Eye; Eye Infections; Eye Injuries; Eyedrops; Failure; Fluorescein; Formulation; Gel; Goals; Hospitals; Hydrogels; Hydrophilic Contact Lenses; Iatrogenesis; Immune response; Implant; In Situ; In Vitro; Infection; Intervention; Keratitis; Knowledge; Lead; Legal patent; Licensing; Life; Lubrication; Mammalian Cell; Measures; Membrane; Natural regeneration; Ointments; Opportunistic Infections; Oryctolagus cuniculus; Pathogenicity; Patients; Peptides; Perforation; Phase; Preparation; Property; Pseudomonas aeruginosa; Resistance development; Risk; Safety; Serum; Shapes; Site; Small Business Innovation Research Grant; Staphylococcus aureus; Steroids; Swelling; Technology; Testing; Time; TimeLine; Tissues; Topical Antibiotic; United States; Validation; Vision; Visit; Visual impairment; Work; antimicrobial; biomaterial compatibility; cell growth; combat; corneal epithelial wound healing; corneal epithelium; corneal regeneration; cost; design; dosage; effective therapy; epithelial wound; improved; in vivo; innovation; manufacturing scale-up; microbial; novel; pathogen; pathogenic bacteria; phase 2 study; pressure; prevent; regenerative; scaffold; self assembly; skin ulcer; technological innovation; tissue regeneration; tissue support frame; transmission process; treatment strategy; visual control; wound; wound closure; wound healing; wound treatment

The goal of this Phase I SBIR proposal is to test the feasibility of an antimicrobial tissue scaffolding hydrogel matrix in eliminating infections of the eye and promoting corneal epithelial wound regeneration. There are approximately 2.4 million eye injuries each year in the United States alone and a failure to promote re-epithelialization in corneal wounds within normal two-week time frame causes persistent corneal epithelial defects (PCED’s). Such defects lead to compromised vision or loss, ocular discomfort, infection, scarring, corneal neovascularization, opacification and perforations. Current treatment strategies for PCED’s involve aggressive lubrication with artificial tears/ointments, bandage contact lens, tarsorrhaphy, topical antibiotics, steroids and amniotic membrane grafting or autologous serum and scleral contact lenses. However, neither antibiotics nor amniotic membrane are sufficient to promote corneal re-epithelialization and wound healing in wounds associated with infections. Hence, there is an unmet clinical need to develop a product to promote corneal wound healing while preventing and eliminating infections. Therefore, we propose here a novel self-assembling tissue scaffolding matrix – G4I to (i) prevent infectious pathogens through a unique mechanism of action that is broad spectrum antibacterial, and (2) promoting tissue regeneration by providing cell attachment sites within the scaffolding matrix. Additionally, G4I can gel in situ and conforms to unique wound shapes and depths easily thereby enabling easy administration. Phase I hypothesis. The Phase I SBIR hypothesis is that G4I antimicrobial regenerative matrix can treat microbial keratitis while promoting corneal epithelial wound healing in vitro and in vivo. Phase I Specific Aims. SA1. Demonstrate safety and biocompatibility of G4I to confirm its safety by performing the Draize rabbit eye test and quantifying gel dwell time in the rabbit cornea. Criterion for acceptance: Demonstrate G4I is safe and biocompatible throughout the in-life period, as measured by a Draize score with swelling, edema, and discharge with a score less than 3. SA2. Demonstrate in vivo antimicrobial efficacy of G4I to eliminate Pseudomonas aeruginosa from infected corneal wounds. Criterion for acceptance: Demonstrate effective clearing of P. aeruginosa from wounds by at least 3 log reductions in G4I treated groups on Day 1, 3 and 7. SA3. Demonstrate in vivo efficacy of G4I to promote healing of corneal epithelial wounds. Criterion for acceptance: Improved rate of wound closure in G4I treated groups compared to controls by visual examination, photographs and a histopathological assessment on Day 14.

第一阶段SBIR提案的目标是测试抗菌组织支架的可行性 水凝胶基质在消除眼部感染和促进角膜上皮创伤中的作用 再生仅在美国，每年就有大约240万眼受伤， 在正常的两周时间范围内促进角膜伤口的上皮再形成 上皮缺陷（PCED）。这些缺陷导致视力受损或丧失、眼部不适、感染， 瘢痕形成、角膜新生血管形成、混浊和穿孔。目前PCED的治疗策略 包括用人工泪液/软膏进行侵蚀性润滑、绷带接触透镜、睑板缝合术、局部 抗生素、类固醇和羊膜移植或自体血清和巩膜接触镜。然而，在这方面， 抗生素和羊膜都不足以促进角膜上皮再生和创伤 与感染有关的伤口愈合。因此，存在未满足的临床需求以开发产品， 促进角膜伤口愈合，同时预防和消除感染。 因此，我们在这里提出了一种新的自组装组织支架基质-G4 I，以（i）防止 感染性病原体通过广谱抗菌的独特作用机制，和（2） 通过在支架基质内提供细胞附着位点来促进组织再生。此外，G4 I 可以在原位胶凝并且容易地符合独特的伤口形状和深度，从而能够容易地给药。 第一阶段假设。I期SBIR假设是G4 I抗菌再生基质可以治疗 同时促进角膜上皮伤口愈合的体外和体内研究。 第一阶段具体目标。 SA 1.证明G4 I的安全性和生物相容性，通过Draize兔眼试验确认其安全性 测试和定量凝胶在兔角膜中的停留时间。验收标准：证明G4 I安全， 通过Draize评分（肿胀、水肿和分泌物）测量，在整个活体期间具有生物相容性 得分低于3分。 SA 2.证明G4 I在体内消除铜绿假单胞菌的抗微生物功效 感染的角膜伤口验收标准：证明有效清除铜绿假单胞菌 在第1、3和7天，G4 I治疗组的伤口至少减少3个对数。 SA 3.证明G4 I促进角膜上皮伤口愈合的体内功效。标准 可接受性：通过目视检查，与对照组相比，G4 I处理组的伤口闭合率提高， 在第14天拍摄照片并进行组织病理学评估。