Cartilage injuries progressively degenerate if left untreated, leading to the onset of osteoarthritis. Clinicalmanagement of partial-thickness cartilage lesions via arthroscopic debridement (removal) and lavage (flushingjoint with fluid) relieve pain but fail to repair or protect the tissue against further degeneration. Intraarticular stemcell injections have gained widespread adoption due to their minimally-invasive nature and the anti-inflammatoryand regenerative potential of stem cells. However, systematic investigations of clinical data have demonstratedthat this approach provides limited repair of the cartilage tissue and highly variable outcomes. Thus, similar todebridement and lavage, MSC injections alone is not enough to repair or halt the progression of tissuedeterioration for most patients. One of the major reasons for this is failure of delivered stem cells to localize tothe site of cartilage injury, which limits their therapeutic efficacy. Moreover, the lack of reinforcement at the siteof tissue damage leaves the cartilage exposed to degenerative overloading, which progressively exacerbatestissue damage. We developed a hyaluronic acid (HA)-based therapeutic termed BioAdhesive that can be locallydelivered to the site of cartilage damage, in a minimally-invasive manner, providing mechanical reinforcementand presenting cell-attachment peptides to enhance localization of delivered stem cells to the site of cartilagerepair. Through the proposed work, we will first evaluate the material stability in a proteinaceous synovial fluidsetting to determine the therapeutic window of the material and second, assess stem cell localization postintraarticular stem cell injection in a load-bearing in vivo environment using a goat model. In Aim 1, cartilageinjuries created in cartilage explants will be treated with the BioAdhesive and incubated in synovial fluid with orwithout the addition of the inflammatory cytokine, interleukin 1β. At varying time points post treatment (up to 28days), bone marrow-derived mesenchymal stem cells (MSCs) will be seeded on treated lesions for 24 hours,and cell attachment, material presence, and tissue reinforcement will be assessed. In Aim 2, four partial thicknesscartilage lesions will be created bilaterally in the trochlear groove of goats and two of the four injuries will receiveBioAdhesive treatment. After surgical closure, labeled MSCs will be delivered to each joint via intraarticularinjection. After 7 days, animals will be euthanized and joint tissues will be assessed for MSC localization whilecartilage tissue will be assessed for cellular and tissue matrix via histological and immunohistological staining.These studies will demonstrate the stability and cell localization potential of the BioAdhesive in a synovial, load-bearing environment, validating the feasibility of our material formulation. The completion of this SBIR Phase Iwould directly set the stage for progression to a Phase II award, which would scale up manufacturing, begingregulatory strategy, and evaluate the long-term in vivo assessment of therapeutic effects. Overall, BioAdhesiveprovides an innovative and impactful strategy to stabilize and preserve damaged cartilage, an approach thatcould be groundbreaking in the management of cartilage injuries. PROJECT NARRATIVE
Acute cartilage injuries are unable to self-heal and progressively degenerate, drastically increasing the risk for
the development of osteoarthritis. Intraarticular stem cell injections can relieve pain in some instances, yet their
ability to efficiently and consistently protect against further degeneration is limited due to poor localization of cells
to the site of injury. We developed a therapeutic that can be delivered locally to treat cartilage injuries that: (1)
reinforces the damaged tissue and (2) increases stem cell attachment to promote regenerative processes, with
the ultimate goal of protecting cartilage from further degeneration. pain relief ; relieve pain ; preservation ; Infrastructure ; stem cell delivery ; progenitor cell delivery ; porcine model ; pig model ; piglet model ; swine model ; Regenerative capacity ; regeneration ability ; regeneration capacity ; regeneration potential ; regenerative potential ; reparative process ; repair model ; Adhesives ; Adoption ; Aftercare ; After Care ; After-Treatment ; post treatment ; Animals ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Attention ; Award ; Biocompatible Materials ; Biomaterials ; biological material ; Bone Marrow ; Bone Marrow Reticuloendothelial System ; Cartilage ; Cartilaginous Tissue ; articular cartilage ; Cell Adhesion ; Cellular Adhesion ; Cells ; Cell Body ; Colorado ; Debridement ; Environment ; Flushing ; Goals ; Growth ; Generalized Growth ; Tissue Growth ; ontogeny ; Hyaluronic Acid ; In Vitro ; Intra-Articular Injections ; Intraarticular Injections ; Interleukin-1 beta ; Beta Proprotein Interleukin 1 ; IL-1 beta ; IL-1 β ; IL-1-b ; IL-1β ; IL1-Beta ; IL1-β ; IL1B Protein ; IL1F2 ; IL1β ; Interleukin 1beta ; Interleukin-1β ; Preinterleukin 1 Beta ; Irrigation ; Lavage ; Nonvaginal irrigation ; Nonvaginal lavage ; irrigation therapy ; lavage therapy ; other than vaginal Douching ; other than vaginal Irrigation ; Joints ; Ligands ; Degenerative polyarthritis ; Degenerative Arthritis ; Osteoarthritis ; Osteoarthrosis ; degenerative joint disease ; hypertrophic arthritis ; osteoarthritic ; Legal patent ; Patents ; Patients ; Peptides ; Psychological reinforcement ; Reinforcement ; Research Personnel ; Investigators ; Researchers ; Research Proposals ; Risk ; Stains ; Staining method ; stem cells ; Progenitor Cells ; Miniature Swine ; Minipigs ; mini pig ; mini-swine ; miniswine ; Synovial Fluid ; Synovia ; Technology ; Time ; Tissues ; Body Tissues ; Translating ; Universities ; Work ; cytokine ; Treatment Cost ; Injury ; injuries ; base ; Label ; improved ; Left ; Site ; Surface ; Acute ; repaired ; repair ; Phase ; Histologic ; Histologically ; Physical activity ; Lesion ; Failure ; Bilateral ; Licensing ; Collaborations ; Intellectual Property ; Therapeutic ; fluid ; liquid ; Liquid substance ; Exposure to ; Attenuated ; Inflammatory ; Deposit ; Deposition ; Nature ; programs ; mechanical ; Mechanics ; Hour ; Complex ; System ; Operative Procedures ; Surgical ; Surgical Interventions ; Surgical Procedure ; surgery ; Operative Surgical Procedures ; interest ; American ; Hydrogels ; Prevention ; Reporting ; Abscission ; Extirpation ; Removal ; Surgical Removal ; resection ; Excision ; Cartilage injury ; Deterioration ; Modeling ; Self Heal ; Xiakucao ; Prunella vulgaris ; Staining and Labeling ; Cell Attachment ; Cell-Matrix Adhesions ; Cell-Matrix Junction ; cartilage repair ; Mesenchymal Progenitor Cell ; Mesenchymal progenitor ; Mesenchymal Stem Cells ; Thickness ; Thick ; Load-Bearing ; Loadbearing ; Weight-Bearing ; Weightbearing ; Weight-Bearing state ; Incubated ; Defect ; Caprine Species ; Goats Mammals ; Goat ; Direct Costs ; in vivo ; Clinical Data ; Clinical Management ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Process ; socioeconomics ; socio-economic ; socio-economically ; socioeconomically ; Therapeutic Effect ; Development ; developmental ; cartilage regeneration ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; Outcome ; innovation ; innovate ; innovative ; minimally invasive ; treatment strategy ; effective therapy ; effective treatment ; regenerative ; manufacturing scale-up ; tissue repair ; cartilage degradation ; cartilage degeneration ; clinical investigation ; Formulation ; histological stains ; histologic stains ; Articulation ; Injections ;
