Sustained low-dose dexamethasone delivery via a PLGA microsphere-embedded agarose implant for enhanced osteochondral repair

• Published in: Acta biomaterialia 2020-01, Vol.102, p.326-340
• Main Authors: Stefani, Robert M., Lee, Andy J., Tan, Andrea R., Halder, Saiti S., Hu, Yizhong, Guo, X. Edward, Stoker, Aaron M., Ateshian, Gerard A., Marra, Kacey G., Cook, James L., Hung, Clark T.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - therapeutic use; Arthralgia; Autografts - transplantation; Biomedical materials; Bone implants; Bone Transplantation; Cartilage; Cartilage (articular); Cartilage, Articular - transplantation; Cattle; Chondrocytes; Collagen; Controlled release; Cytokines; Cytotoxicity; Degradation; Delayed-Action Preparations; Dexamethasone; Dexamethasone - therapeutic use; Dogs; Drug Carriers - chemistry; Hindlimb - surgery; Hydrogels; IL-1β; Inflammation; Inflammatory response; Interleukin 1; Knee; Lymphocytes T; Mechanical properties; Microspheres; Modulus of elasticity; Osteochondral repair; Pain; Polylactic Acid-Polyglycolic Acid Copolymer - chemistry; Polylactide-co-glycolide; Preclinical models; Proteoglycans; Sepharose - chemistry; Surgical implants; Sustained release; Synovial fluid; Targeted drug delivery; Transplants & implants
• ISSN: 1742-7061; 1878-7568
• DOI: 10.1016/j.actbio.2019.11.052

Articular cartilage defects are a common source of joint pain and dysfunction. We hypothesized that sustained low-dose dexamethasone (DEX) delivery via an acellular osteochondral implant would have a dual pro-anabolic and anti-catabolic effect, both supporting the functional integrity of adjacent graft and host tissue while also attenuating inflammation caused by iatrogenic injury. An acellular agarose hydrogel carrier with embedded DEX-loaded poly(lactic-co-glycolic) acid (PLGA) microspheres (DLMS) was developed to provide sustained release for at least 99 days. The DLMS implant was first evaluated in an in vitro pro-inflammatory model of cartilage degradation. The implant was chondroprotective, as indicated by maintenance of Young's modulus (EY) (p = 0.92) and GAG content (p = 1.0) in the presence of interleukin-1β insult. In a subsequent preliminary in vivo experiment, an osteochondral autograft transfer was performed using a pre-clinical canine model. DLMS implants were press-fit into the autograft donor site and compared to intra-articular DEX injection (INJ) or no DEX (CTL). Functional scores for DLMS animals returned to baseline (p = 0.39), whereas CTL and INJ remained significantly worse at 6 months (p