Abstract
Current tissue engineering strategies for treating traumatic or degenerative cartilage defects in osteoarthritis (OA) remain insufficient in promoting robust tissue regeneration while simultaneously addressing inflammation, matrix degradation, and post-surgical infections. In this study, we evaluated the in vivo biocompatibility and regenerative potential of a nanoenabled collagen-polylactide (Col-PLA) scaffold functionalized with tri-combinatorial nanoemulsions delivering ibuprofen (anti-inflammatory), batimastat (BB-94, anti-proteolytic), and mupirocin (anti-bacterial). Using a femoral osteochondral defect model in New Zealand White rabbits, regeneration was assessed at 4- and 12-week post-implantation by macroscopic scoring, biomechanical indentation mapping, and histological analysis. Synovial inflammation was further evaluated via histology, CD8 immunostaining, and quantification of key pro-inflammatory mediators including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), prostaglandin E(2) (PGE(2)), and matrix metalloproteinase-13 (MMP-13). Both functionalized and non-functionalized Col-PLA scaffolds supported significant host cell infiltration and tissue regeneration, outperforming untreated controls and demonstrating effective subchondral bone repair. A transient inflammatory response was observed in the nanoenabled group at 4 weeks, without elevation of synovial pro-inflammatory cytokines or compromised tissue regeneration. Although cartilage repair was comparable between scaffold groups, the nanoenabled Col-PLA scaffold might have a potential benefit in more complex or comorbid clinical scenarios due to its immunomodulatory, anti-proteolytic, and anti-microbial functionalization. The findings of this study support further investigations of these modular scaffolds in OA and infection-prone environments, using disease-relevant and long-term models, to fully establish its therapeutic applicability in regenerative medicine.