Non-Steroidal Anti-inflammatory Drug (NSAID)-Derived Poly(anhydrideesters) in Bone and Periodontal Regeneration

Mark A. Reynolds; Almudena Prudencio; Mary E. Aichelmann-Reidy; Kevin Woodward; Kathryn E. Uhrich

Abstract

Bioresorbable polymers offer the potential to deliver biologically active agents that selectively modulate wound healing in bone and periodontal regeneration. This preliminary study characterizes early wound healing in calvarial defects grafted with demineralized bone matrix (DBM) overlaid with membranes made from a novel class of non-steroidal anti-inflammatory drug (NSAID)-derived poly(anhydride-esters). These polymers chemically incorporate either salicylic acid (SA) or 5-(2,4-difluorophenyl)salicylic acid (diflunisal) into the polymeric backbone and release the NSAIDs upon hydrolysis. Inflammatory cell infiltrate in response to the novel NSAID-derived polymers was compared to defects grafted with DBM alone at 10 days and to defects grafted with DBM and overlaid with poly(lactic acid) (PLA; Atrisorb®) at 21 days in 8 Wistar rats (350-450 g). Histological analysis of the calvarial sites at 10 days revealed that the NSAIDderived polymers were associated with moderate levels of inflammation similar to defects grafted without polymer (2.3 ± 0.96 versus 2.0 ± 0.82, respectively), consistent with the therapeutic activity of salicylic acid and diflunisal. Defects grafted with DBM and overlaid with NSAID-derived polymers at 21 days exhibited mild inflammation; whereas, defects treated with PLA were consistently associated with moderate to severe inflammatory cell infiltrate (1.8 ± 0.50 versus 2.7 ± 0.58, respectively). Histopathological findings, such as foreign body giant cells or fibrous encapsulation, were not observed in any defects with NSAID-derived polymers. Cellular features consistent with bone formation were found in all grafted defects. This novel class of non-steroidal anti-inflammatory drug-derived poly(anhydride-esters) were well tolerated and elicited no demonstrable increase in inflammation, as shown with PLA, during osseous wound healing in a regenerative application.

Keywords: Poly(anhydride-ester), salicylic acid, diflunisal, degradable, human bone graft, Atrisorb®, inflammation, bone growth