Novel biological strategies for treatment of wear particle-induced periprosthetic osteolysis of orthopaedic implants for joint replacement.

Wear particles and by-products from joint replacements and other orthopaedic implants may result in a local chronic inflammatory and foreign body reaction. This may lead to persistent synovitis resulting in joint pain and swelling, periprosthetic osteolysis, implant loosening and pathologic fracture. Strategies to modulate the adverse effects of wear debris may improve the function and longevity of joint replacements and other orthopaedic implants, potentially delaying or avoiding complex revision surgical procedures. Three novel biological strategies to mitigate the chronic inflammatory reaction to orthopaedic wear particles are reported. These include (i) interference with systemic macrophage trafficking to the local implant site, (ii) modulation of macrophages from an M1 (pro-inflammatory) to an M2 (anti-inflammatory, pro-tissue healing) phenotype in the periprosthetic tissues, and (iii) local inhibition of the transcription factor nuclear factor kappa B (NF-κB) by delivery of an NF-κB decoy oligodeoxynucleotide, thereby interfering with the production of pro-inflammatory mediators. These three approaches have been shown to be viable strategies for mitigating the undesirable effects of wear particles in preclinical studies. Targeted local delivery of specific biologics may potentially extend the lifetime of orthopaedic implants.

Efficacy of a p38 mitogen activated protein kinase inhibitor in mitigating an established inflammatory reaction to polyethylene particles in vivo.

The inhibitor of p38 mitogen-activated protein kinase (MAPK) is of interest in the nonoperative treatment of periprosthetic osteolysis due to wear particles. Previous studies demonstrated that an oral p38 MAPK inhibitor did not suppress bone formation when given during the initial phase of tissue differentiation. However, the oral p38 MAPK inhibitor also did not curtail the foreign body and chronic inflammatory response to particles when given simultaneously. The purpose of the current study was to examine the efficacy of a p38 MAPK inhibitor, SCIO-323, on mitigating an established inflammatory reaction that parallels the clinical situation more closely. The Bone Harvest Chamber was implanted in rabbits and submicron polyethylene particles were placed in the chamber for 6 weeks. The contents of the chambers were harvested every 6 weeks. Oral treatment with the SCIO-323 included delivery for 3 weeks and stopping for 3 weeks, delivery for 3 weeks after an initial 3-week delay, and delivery for 6 weeks continuously. Administration of the SCIO-323 continuously for 6 weeks with/without the presence of particles, or for the initial 3 of 6 weeks had minor effects on bone ingrowth. After establishing a particle-induced chronic inflammatory reaction for 3 weeks, administration of SCIO-323 for a subsequent 3 weeks suppressed net bone formation. The activity of osteoclast-like cells remained low among all treatments when compared with the first control. Using the present model, the oral p38 MAPK inhibitor was ineffective in improving bone ingrowth in the presence of polyethylene particles.