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 (PCEDs). Such defects lead to compromised vision or loss, ocular discomfort, infection, scarring, corneal neovascularization, opacification and perforations. Current treatment strategies for PCEDs 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.
Public Health Relevance Statement: Narrative The proposed product G4I is a flowable, antimicrobial tissue scaffolding matrix to promote wound closure and healing of a corneal epithelial wound/ulcer while combating bacterial pathogens. G4I is designed to incorporate three major benefits of wound closure in one product easily applicable, void filling scaffold to promote epithelial cell growth and proliferation while eliminating infections. G4I is a self-assembly matrix , produced synthetically, easy to manufacture and scale-up, is biocompatible with little to no immune response and has a unique mechanism action against which the development of resistance is highly unlikely.
Project Terms: Affect; Animal Model; Anti-Bacterial Agents; Antibiotics; antimicrobial; Antimicrobial Resistance; Artificial Tears; Autologous; Bacteria; Bacterial conjunctivitis; Bacterial Eye Infections; Bandage; biomaterial compatibility; Blindness; cell growth; Cell Proliferation; Cell-Matrix Junction; Cicatrix; Clinical; combat; Complex; Contact Lenses; Cornea; corneal epithelial wound healing; corneal epithelium; Corneal Injury; Corneal Neovascularization; corneal regeneration; cost; Defect; design; Development; dosage; Dyes; Edema; effective therapy; Endophthalmitis; Epithelial; Epithelial Cells; epithelial wound; Epithelium; Exhibits; Extracellular Matrix; Eye; Eye Infections; Eye Injuries; Eyedrops; Failure; Fluorescein; Formulation; Gel; Goals; Hospitals; Hydrogels; Hydrophilic Contact Lenses; Iatrogenesis; Immune response; Implant; improved; In Situ; In Vitro; in vivo; Infection; innovation; Intervention; Keratitis; Knowledge; Lead; Legal patent; Licensing; Life; Lubrication; Mammalian Cell; manufacturing scale-up; Measures; Membrane; microbial; Natural regeneration; novel; Ointments; Opportunistic Infections; Oryctolagus cuniculus; pathogen; pathogenic bacteria; Pathogenicity; Patients; Peptides; Perforation; Phase; phase 2 study; Preparation; pressure; prevent; Property; Pseudomonas aeruginosa; regenerative; Resistance development; Risk; Safety; scaffold; self assembly; Serum; Shapes; Site; skin ulcer; Small Business Innovation Research Grant; Staphylococcus aureus; Steroids; Swelling; technological innovation; Technology; Testing; Time; TimeLine; tissue regeneration; tissue support frame; Tissues; Topical Antibiotic; transmission process; treatment strategy; United States; Validation; Vision; Visit; visual control; Visual impairment; Work; wound; wound closure; wound healing; wound treatment
