SBIR-STTR Award

Due to the Pi's pioneering work over the past decade, amniotic membrane transplantation (AMT) for ocular surface reconstruction was approved by the FDA in 2001 and reimbursed by Medicare in 2004 as a standard surgical procedure. A number of studies have shown that AMT is effective in facilitating epithelial wound healing and reducing stromal inflammation, scarring and unwanted new blood vessel formation. Using the Pi's proprietary method, Bio-Tissue (a subsidiary of TissueTech, Inc.) has distributed more than 10,000 human amniotic membrane products (trademark name: "AmnioGraft") to more than 1,200 ophthalmic surgeons worldwide since 1997. Nevertheless, the AmnioGraft transplantation procedure requires the use of sutures and surgery in an operating room. Previously, we developed a "sutureless" AmnioGraft and received FDA's 510(k) approval for this as a Class II device (2003), trademarked as Prokera, as a first step toward achieving our ultimate objective of performing AMT without sutures to reduce the medical cost and facilitate the ease of patient care, especially for those patients suffering from severe ocular surface destruction such as Stevens Johnson syndrome and chemical burns. In this Phase I application, we present preliminary data to support the feasibility of verifying anti-scarring and anti-inflammatory effects in both water-soluble and lyophilized powder of AM extracts based on our newly reported in vitro assays of TGF-b promoter activity and macrophage apoptosis, respectively. We thus propose another novel approach of delivering AM's inherent anti-inflammatory and anti-scarring effects without being restricted by the sheet configuration of AmnioGraft or Prokera. We would like to compare the relative potency of using collagen or hyaluronic acid as a vehicle to deliver such effects of these two different AM extracts (Aim 1), and to identify the molecular component(s) that is responsible for most, if not all, anti-scarring and anti-inflammatory effects observed in AM stroma (Aim 2). Successful completion of these two aims will allow us to gather critical data for pre-clinical animal testing during the Phase II. We believe that these new technologies will generate new therapeutics to deliver AM's inherent anti-scarring and anti-inflammatory effects to any body site, and help expand our market potential not only in ophthalmology but also in other medical and surgical subspecialties whenever suppressing of tissue inflammation and scarring becomes necessary

Over the past decade, there has been a surge of interest in amniotic membrane transplantation (AMT) for ocular surface reconstruction. A number of studies have shown that AMT using cryopreserved AM (AmnioGraft(R)) manufactured by Bio-Tissue, Inc., a subsidiary of TissueTech, Inc., is effective in facilitating epithelial wound healing and reducing stromal inflammation, scarring and formation of unwanted new blood vessels. To facilitate the ease of patient care and reduce the overall medical cost, we have obtained SBIR Phase I and II grants (R43/R44 EY014768) to develop a ""sutureless"" AM graft so that AMT can be performed in a physician's office or at the bedside of an Intensive Care and Burn Unit without bringing the patient to the operating room. As a result, we have successfully developed ProKera(R), which has received the FDA's 510(k) clearance as a type II medical device. In 2008, we have distributed more than 4,000 units in the U.S. market for treating patients inflicted with a number of sight-threatening corneal surface diseases characterized by poor wound healing, unwanted inflammation, and excessive scarring. We envisioned that AM's inherent anti-inflammatory and anti- scarring actions can further be deployed to treat ocular surface diseases unmanageable by AmnioGraft(R) or ProKera(R), and to any other body sites where inflammation and scarring are of great concern. We further speculated that one solution to the physical constraint of AmnioGraft(R) or ProKera(R) is to develop a gel formulation based on AM extracts (AME). Through SBIR Phase I grant support (R43 EY017497), we have successfully validated the key manufacturing steps of generating AME and its lyophilized powder (AMP), and compared the relative potency of using collagen or hyaluronic acid (HA) as a vehicle to deliver their anti-inflammatory and anti-scarring actions (Aim 1). In addition, we have biochemically purified and characterized one covalent complex (HC7HA) containing HA and heavy chains (HC) of inter-a-inhibitor (IaI) as the active component in AME responsible for most, if not all, anti-inflammatory and anti-scarring effects observed in AM stroma (Aim 2). In Phase II, we thus propose to validate the potency of purified HC7HA complex in exerting in vitro anti-inflammatory and anti-scarring actions, verify the consistency of manufacturing HC7HA complex regarding its biochemical composition and purity, and optimize the HA gel formulation containing HC7HA complex (Aim 1). In addition, we propose to demonstrate clinical efficacies of the aforementioned gel formulation containing HC7HA complex in exerting an anti-inflammatory action in a murine model of HSV1-induced necrotizing stromal keratitis, and an anti-scarring action in a rabbit model of excimer laser-assisted photorefractive keratectomy (PRK) (Aim 2). Successful completion of the above two Aims will allow us to gather sufficient and pertinent data for IDE/IND submission to the FDA so that we may begin to commercialize the first ophthalmic topical formulation and continue to build a pipeline of new therapeutics based on AME or purified HC7HA complex so that we may expand our market spaces not only in ophthalmology, but also in other medical and surgical subspecialties. , ,

Public Health Relevance:
This application proposes to develop a novel pipeline of therapeutics based on anti-inflammatory and anti-angiogenic actions of amniotic membrane extract as well as its purified covalent complex containing hyaluronan and heavy chains of inter-a-inhibitor. Successful completion of our proposed studies in Phase II will allow us to gather sufficient and pertinent data for IDE/IND submission to the FDA so that we may begin to commercialize the first ophthalmic topical formulation and expand our market spaces not only in ophthalmology, but also in other medical and surgical subspecialties.

Thesaurus Terms:
Anti-Inflammatories;Anti-Inflammatory Agents;Anti-Inflammatory;Antiinflammatories;Antiinflammatory Agents;Biochemical;Blood Vessels;Body Tissues;Burn Units;Cicatrix;Clinical;Codes, Cpt;Collagen;Complex;Cornea;Current Procedural Terminology Codes;Data;Disease;Disorder;Drug Formulations;Electromagnetic, Laser;Epithelial;Figs;Figs - Dietary;Formulation;Formulations, Drug;Gel;Grant;Hhv-1;Hosp;Hsv-1;Hsv1;Health Insurance For Aged And Disabled, Title 18;Health Insurance For Aged, Title 18;Health Insurance For Disabled Title 18;Herpes Simplex Virus 1;Herpes Simplex Virus Type 1;Herpesvirus 1 (Alpha), Human;Herpesvirus 1, Human;Hospitals;Human Herpes Simplex Virus Type 1;Human Herpesvirus 1;Human Herpesvirus Type 1;Hyaluronan;Hyaluronic Acid;Inflm;In Vitro;Inflammation;Intensive Care;Investigators;Keratectomy, Laser;Keratitis;Lasers;Mammals, Mice;Mammals, Rabbits;Marketing;Medical;Medical Device;Medicare;Membrane;Mice;Modeling;Murine;Mus;Operating Rooms;Operation;Operative Procedures;Operative Surgical Procedures;Ophthalmology;Oryctolagus Cuniculus;Paper;Patient Care;Patient Care Delivery;Patients;Phase;Photokeratectomy;Photorefractive Keratectomy;Physicians' Offices;Powder Dose Form;Powders;Progress Reports;Pubmed;Publishing;R43 Grant;Rabbit, Domestic;Rabbits;Radiation, Laser;Relative;Relative (Related Person);Research Personnel;Researchers;Sbir;Sbirs (R43/44);Scars;Sight;Site;Small Business Innovation Research;Small Business Innovation Research Grant;Solutions;Surface;Surgical;Surgical Interventions;Surgical Procedure;Therapeutic;Tissues;Title 18;Transplantation;Vision;Wound Healing;Wound Repair;Base;Clinical Applicability;Clinical Application;Clinical Efficacy;Corneal;Cost;Disease/Disorder;Health Insurance For Disabled;Herpes Simplex I;Herpes Virus 1, Human;Human Alphaherpesvirus 1;Inhibitor;Inhibitor/Antagonist;Interest;Membrane Structure;New Therapeutics;Next Generation Therapeutics;Novel;Novel Therapeutics;Ocular Surface;Public Health Relevance;Reconstruction;Surgery;Tissue Repair;Transplant;Vascular