Total joint replacement (TJR) is a highly successful surgical procedure however the long-term survivorship is limited by wear of the bearing surfaces. Monocyte Chemoattractant Protein-1 (MCP-1) is the most important chemokine regulating systemic and local trafficking of monocyte/macrophages in inflammation. In vitro, in vivo and tissue retrieval studies have demonstrated a critical role for MCP-1 in wear particle-induced inflammation. The goals of this grant proposal are twofold 1) to develop, functionalize and validate a novel orthopaedic implant nano-coating that will deliver anti-MCP-1 protein therapy to the implant-bone interface and 2) to modulate macrophage polarization at the interface from an M1 (pro-inflammatory) to an M2 (pro- tissue remodeling and angiogenesis) phenotype with local infusion of the anti-inflammatory cytokine Interleukin-4 (IL-4). Both of these strategies will decrease chronic inflammation near the implant, improve bone apposition, and decrease particle-induced bone loss due to continuous local infusion of wear particles using our established in vivo murine model.
Specific Aim #1 : To construct, optimize and validate a local delivery system in which mutant anti-MCP-1 protein (called 7ND protein) is eluted from a titanium rod in vitro.
Specific Aim #2 : To demonstrate that local delivery of 7ND protein decreases systemic macrophage trafficking to the protein eluting titanium implant, thereby improving bone apposition and decreasing peri- implant osteolysis, using the murine continuous polyethylene particle infusion model.
Specific Aim #3 : To demonstrate that transformation of macrophages located at the bone-implant interface in the presence of continuously infused polyethylene particles from an M1 (pro-inflammatory) to an M2 (pro- tissue remodeling and angiogenesis) phenotype with local delivery of IL-4 will decrease bone loss and improve bone apposition adjacent to the implant. The proposed studies aspire to modulate the inflammatory reaction to polymer wear particles using a murine model of continuous polyethylene particle infusion, similar to the clinical scenario in humans. Strategies which target macrophage migration (delivery of a mutant MCP-1 protein near the implant) and alter the phenotype of local peri-implant macrophages to one supporting tissue remodeling and angiogenesis (local infusion of IL-4) will be tested. The techniques of bioluminescence, microCT and micro PET scanning, histology and morphometry will be used to delineate systemic trafficking of macrophages to the particles, the characteristics of the local inflammatory reaction, and development or prevention of osteolysis. Both of the biological strategies proposed are novel, mechanistic and directly translational;they should result in decreased peri-implant inflammation, improved bone apposition and decreased particle-induced bone loss, potentially extending the lifetime of joint replacements.

Public Health Relevance

Total joint replacement (TJR) is a highly successful surgical procedure for end-stage arthritis however the longevity of TJRs is limited by wear of the bearing surfaces. Wear particles stimulate a chronic inflammatory reaction that causes local bone destruction around the implant. The purpose of this grant is to test two novel translational strategies to mitigate particle-associated bone destruction by interfering with inflammatory cell signaling, and transforming the inflammatory cells to cells favoring tissue regeneration. Both strategies have a high likelihood of extending the lifetime of TJRs in humans.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Panagis, James S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
Lin, Tzu-Hua; Kao, Sunny; Sato, Taishi et al. (2015) Exposure of polyethylene particles induces interferon-? expression in a natural killer T lymphocyte and dendritic cell coculture system in vitro: a preliminary study. J Biomed Mater Res A 103:71-5
Pajarinen, Jukka; Tamaki, Yasunobu; Antonios, Joseph K et al. (2015) Modulation of mouse macrophage polarization in vitro using IL-4 delivery by osmotic pumps. J Biomed Mater Res A 103:1339-45
Goodman, S B; Gibon, E; Pajarinen, J et al. (2014) Novel biological strategies for treatment of wear particle-induced periprosthetic osteolysis of orthopaedic implants for joint replacement. J R Soc Interface 11:20130962
Lin, Tzu-Hua; Yao, Zhenyu; Sato, Taishi et al. (2014) Suppression of wear-particle-induced pro-inflammatory cytokine and chemokine production in macrophages via NF-?B decoy oligodeoxynucleotide: a preliminary report. Acta Biomater 10:3747-55
Lin, Tzu-hua; Tamaki, Yasunobu; Pajarinen, Jukka et al. (2014) Chronic inflammation in biomaterial-induced periprosthetic osteolysis: NF-*B as a therapeutic target. Acta Biomater 10:1-10
Pajarinen, J; Lin, T-H; Sato, T et al. (2014) Interaction of Materials and Biology in Total Joint Replacement - Successes, Challenges and Future Directions. J Mater Chem B Mater Biol Med 2:7094-7108
Gallo, Jiri; Vaculova, Jana; Goodman, Stuart B et al. (2014) Contributions of human tissue analysis to understanding the mechanisms of loosening and osteolysis in total hip replacement. Acta Biomater 10:2354-66
Keeney, Michael; Waters, Heather; Barcay, Katherine et al. (2013) Mutant MCP-1 protein delivery from layer-by-layer coatings on orthopedic implants to modulate inflammatory response. Biomaterials 34:10287-95
Goodman, Stuart B; Yao, Zhenyu; Keeney, Michael et al. (2013) The future of biologic coatings for orthopaedic implants. Biomaterials 34:3174-83
Antonios, Joseph K; Yao, Zhenyu; Li, Chenguang et al. (2013) Macrophage polarization in response to wear particles in vitro. Cell Mol Immunol 10:471-82

Showing the most recent 10 out of 26 publications