Osteoarthritis (OA) is a significant contributor to human morbidity and mortality with an economic burden exceeding $30 billion annually in the United States. Lubricin is a natural lubricant of the articular cartilage of the knee, and the intraarticular administration of lubricin prevents OA progression following knee injury. However, the manufacture of lubricin exceeds $10,000/mg, making it an economically impractical product candidate. Recently, a team of biomedical engineers at Cornell University discovered and reduced to practice a synthetic analog of lubricin that prevents OA progression and exhibits excellent biocompatibility in the ACL transection model in rat knees. This lubricin analog, Lubrisynth(r), mimics the structure and function of native lubricin, with the added advantage that cost models indicate commercially viable pricing can be expected with further development. The objective of the proposed research is to advance the translation of Lubrisynth(r) toward clinical use to prevent the progression of osteoarthritis (OA) in the knee. The following Specific Aims are defined to advance the preclinical development of Lubrisynth(r) through the Phase 1 STTR mechanism which is an integrated collaboration between experts at Articulate Biomedical, LLC and Cornell University. Specific Aim 1: Scale-up synthesis of Lubrisynth(r) to the 100 g pilot scale. Lubrisynth(r) is a brush copolymer consisting of a poly acrylic acid backbone with polyethylene glycol sidechains. The synthetic route was designed to allow facile and controlled scale-up in only two steps. The objective of Specific Aim 1 is to apply full factorial experimental design and analysis to establish the scaled process tolerability and the driving factor levels necessary for the reproducible 100 gram-scale synthesis of Lubrisynth(r). The anticipated outcome is a robust quantitated tolerance protocol for the synthesis of Lubrisynth(r) that is amenable to GMP grade manufacture. Specific Aim 2: Establish the in vitro and in vivo biocompatibility profiles of Lubrisynth(r). Lubrisynth(r) will be developed as a Class III medical device. The Industry Guidance for the PMA development pathway of Class III medical devices (i.e., ISO-10993) outlines the specific biocompatibility tests required for implanted devices in contact with tissue/bone for longer than 30 days. In vitro biocompatibility evaluation and in vivo biocompatibility evaluation will be completed as defined by the ISO Guidance. The objective of Specific Aim 2 is to complete both the in vitro and in vivo biocompatibility evaluations of Lubrisynth(r) in accordance with the FDA-accepted guidelines. The anticipated outcome is a thorough and successful analysis of the initial biocompatibility profile of Lubrisynth(r). Collectively, the anticipated outcomes of the proposed work will establish the necessary foundation to begin the commercial development of Lubrisynth(r), and if successful, will clear the way for the STTR Phase 2 Specific Aims (GMP synthesis and clinical efficacy studies).
Public Health Relevance Statement: Public Health Relevance: Osteoarthritis is a significant contributor to human morbidity and reduced quality-of-life. Its economic impact in the United States exceeds $30 billion annually. Our research team has designed and reduced to practice a synthetic lubricant, Lubrisynth(r), that effectively prevents osteoarthritis progression in the rat knee ACL transection model. The objective of the proposed work is to complete both the scale-up synthesis and initial biocompatibility profile of Lubrisynth(r) to facilitate its progression toward human clinical trial.
Project Terms: acrylic acid; Acute; Adhesions; analog; Animals; articular cartilage; Automobile Driving; base; Biocompatible Materials; biomaterial compatibility; Biomedical Engineering; Bone Tissue; Canis familiaris; Cavia; Cell Culture Techniques; Clinical; clinical efficacy; Clinical Sciences; Clinical Trials; Collaborations; college; Complement Activation; copolymer; cost; Counseling; cytotoxicity; Data; Degenerative polyarthritis; design; Development; Disease Progression; Economic Burden; economic impact; Evaluation; Exhibits; experimental analysis; Experimental Designs; eye dryness; Fingers; Foundations; genotoxicity; Grant; Guidelines; Hip region structure; Human; human morbidity; human mortality; Hyaluronic Acid; Implant; implantable device; implantation; In Vitro; in vivo; Industry; Intra-Articular Injections; irritation; Knee; Knee Injuries; Knee Osteoarthritis; Laboratories; long bone; Lubricants; Lubrication; lubricin; Marketing; Medical Device; meetings; Modeling; Orthopedic Surgery procedures; Outcome; palliative; Pathway interactions; Phase; Play; Polyethylene Glycols; pre-clinical; prevent; Price; Process; product development; programs; Protocols documentation; public health relevance; Quality of life; Rattus; Research; Research Personnel; research study; Rodent; Role; Route; scale up; Small Business Technology Transfer Research; Spinal; Structure; success; Surface; Surgeon; Temporomandibular Joint Disorders; Testing; Toxic effect; Translations; United States; Universities; Vertebral column; Veterinary Medicine; Work
