Modulation of bone ingrowth and tissue differentiation by local infusion of interleukin-10 in the presence of ultra-high molecular weight polyethylene (UHMWPE) wear particles Stuart Goodman, 1 Michael Trindade, 1 Ting Ma, 1 Mel Lee, 1 Neal Wang, 1 Takashi Ikenou, 1 Ippe Matsuura, 1 Keita Miyanishi, 1 Nora Fox, 1 Donald Regula, 2 Mark Genovese, 3 John Klein, 4 Dan Bloch, 3 R. Lane Smith 1 1 Division of Orthopaedic Surgery, Stanford University Medical Center, 300 Pasteur Drive, Stanford, California 94305 2 Department of Pathology, Stanford University Medical Center, Stanford, California 94305 3 Division of Immunology and Rheumatology, Stanford University Medical Center, Stanford, California 4 Alza Corp., Palo Alto, California Received 11 January 2002; accepted 19 February 2002 Abstract: Interleukin-10 (IL-10) is a cytokine that plays a major role in suppressing the inflammatory response, par- ticulary cell-mediated immunity that is characteristic of the TH1 response. The purpose of this study was to determine whether local infusion of IL-10 could mitigate the suppres- sion of bone ingrowth associated with polyethylene wear particles. Drug test chambers were implanted in the proxi- mal tibia of 20 mature New Zealand white rabbits. The DTC provided a continuous 1 × 1 × 5-mm canal for tissue in- growth. After a 6-week period for osseointegration, the DTC was then connected to an osmotic diffusion pump. IL-10 at doses of 0.1–100 ng/mL (0.25 L/h) was infused with or without ultra-high molecular weight polyethylene particles (0.5 ± 0.2 m diameter, 10 12 particles/mL) present in the chamber for a 3- or 6-week period. The tissue in the chamber was harvested after each treatment; sections were stained with hematoxylin and eosin for morphometric analysis. Os- teoclast-like cells were identified by immunohistochemical staining using a monoclonal antibody directed against the alpha chain of the vitronectin receptor, CD51. Osteoblasts were identified using alkaline phosphatase staining. In dose–response studies, infusion of 1 ng/mL IL-10 yielded the greatest bone ingrowth in the presence of particles. The addition of polyethylene particles evoked a marked foreign body reaction and fibrosis; bone ingrowth was significantly suppressed (p = 0.0003). Bone ingrowth was increased by over 48% with infusion of IL-10 for the final 3 weeks of a 6-week ultra-high molecular weight polyethylene particle exposure compared with particles alone (p = 0.027). IL-10 is a cytokine that plays a major role in suppressing the inflam- matory response, especially cell-mediated immunity that is characteristic of the TH1 response. Local infusion of im- mune-modulating cytokines such as IL-10 may prove to be useful in abating particle-induced periprosthetic osteolysis. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 65A: 43– 50, 2003 Key words: total joint replacement; bone ingrowth; anti- inflammatory cytokine; interleukin-10; polyethylene par- ticles INTRODUCTION The main factor limiting long-term survivorship of total joint replacements is prosthetic wear, the produc- tion of particulate debris, and subsequent peripros- thetic osteolysis. 1 Osteolysis may occur with or with- out prosthetic loosening and usually is a silent disease clinically. Despite improvements in prosthetic design and materials, surgical technique, patient selection, and education, revision surgery is still common and constitutes 25% or more of the arthritis caseload in some university institutions. 1,2 Polyethylene (PE) particles may adversely affect both initial osseointegration and subsequent bone re- modeling of a total joint replacement. 1,3–7 Immediately after implanting a total joint replacement, the bone– prosthesis interface is exposed continuously to PE wear particles specific to the biomaterials implanted. The inflammatory and foreign body reaction to this debris may interfere with initial prosthetic osseointe- Correspondence to: S. B. Goodman; e-mail: goodbone@ stanford.edu Contract grant sponsor: Arthritis Foundation Contract grant sponsor: Alza Corp Contract grant sponsor: Pharmacia © 2003 Wiley Periodicals, Inc.