SBIR-STTR Award

Ulcerative keratitis caused by infectious microbes (bacteria, fungi, amoebae and viruses) represents a major area of medical concern. It is one of the most important causes of corneal opacifications, which is the second common cause of legal blindness world-wide after cataracts. In 2010, in the USA alone, 76.5% of the approximately 930,000 doctor's office and outpatient clinic and 58,000 emergency department visits related to ocular distress and emergencies, resulted in antibiotic prescriptions for microbil keratitis. The total annual financial burden on our healthcare system for keratitis cases was estimated to be $175 million in direct health care expenditures in 2010 and was also estimated to consume over 250,000 annual hours of clinician time. Bacterial keratitis manifests as corneal ulcer, corneal edema and/or hypopyon and can cause significant complications including corneal perforation, corneal thinning, elevated intraocular pressure and progression to endophthalmitis. This could lead to severe clinical outcomes including partial or complete vision loss, necessity for penetrating keratoplasty, corneal grafts, enucleation and evisceration. Although topical and systemic antibiotics are effective in reducing microbial loads in keratitis cases (unless the microbe is resistant to the antibiotic utilized), the time required to resolve th infection is generally quite lengthy. Furthermore, antibiotics are typically ineffective in reducin inflammation and evoking regenerative repair of corneal and/or scleral defects and scarring which may be induced by the infection. Lynntech, Inc. in collaboration with the University of Mississippi Medical Center proposes to develop an innovative, inexpensive and compact device, termed iCAP to effectively treat microbial keratitis at the point-of-diagnosis. This device will be engineered to rapidly and reagentlessly significantly reduce or totally eliminate bacterial loads regardless of antimicrobial susceptibility status of the infecting microbial species. Furthermore, iCAP has the potential to simultaneously trigger certain cellular signaling pathways which could result in improved regeneration of corneal and scleral defects induced by the infection. During this Phase I SBIR effort, our specific aims are to (1) design and fabricate prototype iCAP devices, (2) utilize in vitro microbial and mammalian cell culture techniques to obtain pilot ranges of iCAP device operating parameters likely to be effective in vivo and (3) demonstrate that iCAP can significantly reduce or eliminate bacterial loads and orchestrate healing of infection induced corneal/scleral defects in a relevant in vivo rabbit eye model of bacterial keratitis. The successful completion of these specific aims should demonstrate ample feasibility of this innovative new microbial keratitis treatment approach, and will enable us to execute more comprehensive technology development and commercialization thrusts in a future follow-on Phase II effort. The eventual commercial availability of iCAP devices is likely to sustai high positive impact for the patient populace suffering from microbial keratitis.

Public Health Relevance Statement:


Public Health Relevance:
The potential long-term impact of this SBIR effort is an effective new paradigm in the treatment of microbial keratitis right at the point-of-diagnosis. Our envisioned automated iCAP devices have the potential to not only resolve the infection in a faster timeframe than with the use of antibiotics, but also heal eye defects induced as a consequence of the infection. iCAP could thus provide significant clinical benefit for microbial keratitis patients worldwide and enable faster healing coupled with lowered costs of treatment.

Project Terms:
Accounting; Adhesions; Outpatient Clinics; Ambulatory Care Facilities; Amoeba; Amoeba genus; Miscellaneous Antibiotic; Antibiotic Drugs; Antibiotic Agents; Antibiotics; Ar element; Argon; Bacteria; cell culture; Cell Culture Techniques; Scars; Cicatrix; Coagulase; corneal; Cornea; cornea edema; Corneal edema; corneal transplant; corneal keratoplasty; Corneal Transplantation; Corneal Grafting; Cornea Transplantation; Keratoplasty; corneal ulceration; cornea ulcer; Ulcerative Keratitis; Corneal Ulcer; Diagnosis; Disorder; Disease; DNA Injury; DNA Damage; Hydrops; Dropsy; Edema; Emergencies; Emergency Situation; Ophthalmia; Endophthalmitis; Engineering; Expenditure; health care expenditure; Health Expenditures; Eyeball; Eye; fungus; Future; Gases; Health Care Systems; Healthcare Systems; He element; Helium; Hydroperoxide; H2O2; Hydrogen Peroxide; In Vitro; Infection; Inflammation; interferon beta 2; Plasmacytoma Growth Factor; Myeloid Differentiation-Inducing Protein; MGI-2; IL6 Protein; IL-6; IFNB2; IFN-beta 2; Hybridoma Growth Factor; Hepatocyte-Stimulating Factor; HPGF; BSF2; BSF-2; BCDF; B-Cell Stimulatory Factor-2; B-Cell Differentiation Factor-2; B-Cell Differentiation Factor; B cell stimulating factor 2; B cell differentiation factor; Interleukin-6; Ocular Tension; Intraocular Pressure; Physiologic Intraocular Pressure; Keratitis; Penetrating Keratoplasty; heavy metal lead; heavy metal Pb; Pb element; Lead; Photoradiation; Light; Lipid Peroxidation; Cell Membrane Lipids; Membrane Lipids; Methods; Mississippi; N2 element; N element; Nitrogen; O2 element; O element; Oxygen; Patients; Reticuloendothelial System, Serum, Plasma; Plasma Serum; Blood Plasma; Plasma; Pseudomonas pyocyanea; P.aeruginosa; P. aeruginosa; Pseudomonas aeruginosa; Rabbits Mammals; Rabbits; Domestic Rabbit; Oryctolagus cuniculus; proto-oncogene protein c-erbB-1; erbBl; erbB-1 Proto-Oncogene Protein; erbB-1; c-erbB-1 Protein; c-erbB-1; Urogastrone Receptor; Transforming Growth Factor alpha Receptor; TGF-alpha Receptor; HER1; Epidermal Growth Factor-Urogastrone Receptors; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Epidermal Growth Factor Receptor Kinase; ERBB Protein; EGFR; EGF Receptor; Epidermal Growth Factor Receptor; regenerate; Regeneration; Natural regeneration; Safety; Signal Pathway; Staphylococcus; Genus staphylococcus; Staph aureus; S.aureus; S. aureus; Staphylococcus aureus; Streptococcus; S. pneumoniae; Pneumococcus; Diplococcus pneumoniae; D.pneumoniae; D. pneumoniae; Streptococcus pneumoniae; Time; Universities; Virus; General Viruses; Weight; cytokine; Vinculin; metavinculin; Antibiotic Resistance; antibiotic resistant; Resistant to antibiotics; Resistance to antibiotics; Healthcare; health care; Cataract; cataractous lenses; cataractogenesis; Treatment Cost; Killings; improved; Area; Clinical; Healed; repair; repaired; Phase; Medical; Ensure; Distress; data repository; clinical data repository; Databanks; Data Bases; Data Banks; Databases; Ophthalmologist; Legal Blindness; Collaborations; Staging; Antimicrobial susceptibility; Hour; visual loss; vision loss; Blindness; Perforation; Emergency room; Emergency Department; Accident and Emergency department; Medical center; Cellular Proliferation; Cell Multiplication; Cell Growth in Number; Cell Proliferation; Performance; technology development; microbial; Chemical Exposure; Devices; Coding System; Code; Regulation; Modeling; Focal Contacts; Cell-Matrix Adherens Junctions; Adhesion Plaques; Focal Adhesions; b-ENAP; TSG-1; SCYB8; MONAP; MDNCF; LYNAP; LUCT; K60; IL8; IL-8; GCP1; CXCL8; AMCF-I; 3-10C; IL8 gene; pp125FAK; PTK2; FAK1; FAK; FADK; PTK2 gene; Defect; Bacterial Model; Data; Mammalian Cell; Resolution; in vivo; in vivo Model; Small Business Innovation Research; SBIR; Small Business Innovation Research Grant; resistant mechanism; resistance mechanism; preclinical; pre-clinical; healing; corneal repair; designing; design; efficacy evaluation; Outcome; Population; migration; Trauma; Coupled; innovation; innovative; innovate; Microbe; prototype; commercialization; public health relevance; regenerative; Emergency department visit; Emergency room visit; Emergency care visit; ER visit; ED visit

Ulcerative keratitis caused by infectious microbes (bacteria, fungi, amoebae and viruses) represents a major area of medical concern. It is one of the most important causes of corneal opacifications, which is the second common cause of legal blindness world-wide after cataracts. In 2010, in the USA alone, 76.5% of the approximately 930,000 doctor's office and outpatient clinic and 58,000 emergency department visits related to ocular distress and emergencies, resulted in antibiotic prescriptions for microbial keratitis. The total annual financial burden on our healthcare system for keratitis cases was estimated to be $175 million in direct health care expenditures in 2010 and was also estimated to consume over 250,000 annual hours of clinician time. Bacterial keratitis manifests as corneal ulcer, corneal edema and/or hypopyon and can cause significant complications including corneal perforation, corneal thinning, elevated intraocular pressure and progression to endophthalmitis. This could lead to severe clinical outcomes including partial or complete vision loss, necessity for penetrating keratoplasty, corneal grafts, enucleation and evisceration. Although topical and systemic antibiotics are effective in reducing microbial loads in keratitis cases (unless the microbe is resistant to the antibiotic utilized), the time required to resolve the infection is generally quite lengthy. Furthermore, antibiotics are typically ineffective in reducing inflammation and evoking regenerative repair of corneal and/or scleral defects and scarring which may be induced by the infection. In the preceding SBIR Phase I effort, Lynntech, Inc. in collaboration with the University of Mississippi Medical Center has obtained proof-of-concept for the potential clinical utility of an innovative, inexpensive and compact device, termed iCAP to effectively treat microbial keratitis at the point-of-diagnosis. We now propose this follow-on Phase II SBIR effort, where our specific aims are to (1) optimize and finalize iCAP device design, (2) comprehensively elucidate mechanisms of action of iCAP and (3) comprehensively demonstrate pre-clinical safety and efficacy of iCAP using relevant in vivo animal models of microbial keratitis and (4) research FDA requirements to enable IDE application and human trials in future phases of this effort. The successful completion of these specific aims should pave the way for FDA clearance and commercial insertion into ophthalmologic practice of affordable iCAP devices to effectively treat microbial keratitis at the point-of-diagnosis which in turn is likely to sustain high positive impact for the patient populace suffering from microbial keratitis.

Public Health Relevance Statement:
PROJECT NARRATIVE The potential long-term impact of this SBIR effort is an effective new paradigm in the treatment of microbial keratitis right at the point-of-diagnosis. Our envisioned automated iCAP devices have the potential to not only resolve the infection in a faster timeframe than with the use of antibiotics, but also heal eye defects induced as a consequence of the infection. iCAP could thus provide significant clinical benefit for microbial keratitis patients worldwide and enable faster healing coupled with lowered costs of treatment.

Project Terms:
Air; Ambulatory Care Facilities; Outpatient Clinics; Amoeba genus; Amoeba; Antibiotics; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Bacteria; Cell Adhesion; Cellular Adhesion; cell motility; Cell Locomotion; Cell Migration; Cell Movement; Cellular Migration; Cellular Motility; Motility; Cells; Cell Body; Cicatrix; Scars; Clinical Trials; Coagulase; Cornea; corneal; Corneal edema; cornea edema; Keratoplasty; Cornea Transplantation; Corneal Grafting; Corneal Transplantation; corneal keratoplasty; corneal transplant; Corneal Ulcer; Ulcerative Keratitis; cornea ulcer; corneal ulceration; Diagnosis; Disease; Disorder; DNA Damage; DNA Injury; Edema; Dropsy; Hydrops; Emergency Situation; Emergencies; Endophthalmitis; Ophthalmia; Health Expenditures; health care expenditure; healthcare expenditure; Eye; Eyeball; fungus; Future; Gases; Healthcare Systems; Health Care Systems; Helium; He element; Human; Modern Man; Hydrogen Peroxide; H2O2; Hydroperoxide; In Vitro; Infection; Inflammation; Interleukin-6; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; HPGF; Hepatocyte-Stimulating Factor; Hybridoma Growth Factor; IFN-beta 2; IFNB2; IL-6; IL6 Protein; MGI-2; Myeloid Differentiation-Inducing Protein; Plasmacytoma Growth Factor; interferon beta 2; Physiologic Intraocular Pressure; Intraocular Pressure; Ocular Tension; intra-ocular pressure; Ions; Keratitis; Penetrating Keratoplasty; Lead; Pb element; heavy metal Pb; heavy metal lead; Mississippi; Nitrogen; Ophthalmology; Oxygen; O element; O2 element; Patients; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Pseudomonas aeruginosa; P aeruginosa; P. aeruginosa; Pseudomonas pyocyanea; Oryctolagus cuniculus; Domestic Rabbit; Rabbits; Rabbits Mammals; Epidermal Growth Factor Receptor; EGF Receptor; EGFR; ERBB Protein; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Epidermal Growth Factor-Urogastrone Receptors; HER1; TGF-alpha Receptor; Transforming Growth Factor alpha Receptor; Urogastrone Receptor; c-erbB-1; c-erbB-1 Protein; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; proto-oncogene protein c-erbB-1; Research; Safety; Genus staphylococcus; Staphylococcus; Staphylococcus aureus; S aureus; S. aureus; Staph aureus; Streptococcus pneumoniae; D pneumoniae; D. pneumoniae; Diplococcus pneumoniae; Pneumococcus; S pneumoniae; S. pneumoniae; Thinness; Leanness; Time; Ultraviolet Rays; Actinic Rays; UV light; UV radiation; UV rays; ultra violet light; ultra violet radiation; ultra violet rays; ultraviolet light; ultraviolet radiation; Universities; Virus; Interleukin-10; CSIF; CSIF-10; Cytokine Synthesis Inhibitory Factor; IL-10; IL10; IL10A; Interleukin 10 Precursor; Antibiotic Resistance; Resistance to antibiotics; Resistant to antibiotics; antibiotic drug resistance; antibiotic resistant; Device Designs; Healthcare; health care; Cataract; cataractogenesis; cataractous lenses; Treatment Cost; Proto-Oncogene Proteins c-akt; AKT; Akt protein; Protein Kinase B; RAC-PK protein; c-akt protein; proto-oncogene protein RAC; proto-oncogene protein akt; rac protein kinase; related to A and C-protein; improved; Area; Clinical; repaired; repair; Phase; Medical; Distress; Databases; Data Bases; data base; Ophthalmologist; Legal Blindness; Collaborations; Viridans Streptococci; viridans group streptococci; Streptococcus Viridans Group; Hour; vision loss; visual loss; Blindness; Perforation; Emergency Department; Emergency room; Accident and Emergency department; Medical center; Cell Growth in Number; Cell Multiplication; Cellular Proliferation; Cell Proliferation; Animal Models and Related Studies; model of animal; model organism; Animal Model; microbial; Devices; Regulation; Modeling; Adhesion Plaques; Cell-Matrix Adherens Junctions; Focal Contacts; Focal Adhesions; 3-10C; AMCF-I; CXCL8; GCP1; IL-8; IL8; K60; SCYB8; TSG-1; b-ENAP; IL8 gene; ERK 1; ERK1; ERK1 Kinase; Extracellular Signal-Regulated Kinase 1; MAP Kinase 3; MAPK3; MAPK3 Mitogen-Activated Protein Kinase; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase 3 Gene; P44ERK1; PSTkinase p44mpk; p44 MAPK; MAPK3 gene; Antimicrobial resistant; Resistance to antimicrobial; anti-microbial resistance; anti-microbial resistant; resistance to anti-microbial; resistant to anti-microbial; resistant to antimicrobial; Antimicrobial Resistance; Defect; Bacterial Model; Cytokine Activation; pre-clinical testing; Preclinical Testing; Resolution; in vivo; in vivo Model; Clinical Treatment; trial regimen; trial treatment; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; healing; corneal repair; Outcome; PI3K/AKT; PI-3K/AKT; Consumption; Coupled; innovation; innovate; innovative; antimicrobial; anti-microbial; Microbe; prototype; preclinical safety; pre-clinical safety; Emergency department visit; ED visit; ER visit; Emergency care visit; Emergency hospital visit; Emergency room visit; Financial Hardship; financial burden; financial distress; financial strain; financial stress; regenerative repair