title: An experimental animal model of aseptic loosening of hip prostheses in sheep to study early biochemical changes at the interface membrane.
abstract: BACKGROUND
  Aseptic loosening of hip prosthesis as it occurs in clinical cases in human patients was attributed to wear particles of the implants, the response of the tissue dominated by macrophages and the production of inflammatory mediators and matrix degrading enzymes; however, the cascade of events initiating the process and their interaction regarding the time course is still open and discussed controversially. Therefore, the goal of this study was to establish an experimental animal model in sheep allowing to follow the cascade of early mechanical and biochemical events within the interface membrane and study the sequence of how they contribute to the pathological bone resorption necessary for aseptic loosening of the implant.
  
  
  METHODS
  A cemented modular system (Biomedtrix) was used as a hip replacement in 24 adult Swiss Alpine sheep, with one group receiving a complete cement mantle as controls (n = 12), and the other group a cement mantle with a standardized, lateral, primary defect in the cement mantle (n = 12). Animals were followed over time for 2 and 8.5 months (n = 6 each). After sacrifice, samples from the interface membranes were harvested from five different regions of the femur and joint capsule. Explant cell cultures were performed and supernatant of cultures were tested and assayed for nitric oxide, prostaglandin E2, caseinolytic and collagenolytic activity. RNA extraction and quantification were performed for inducible nitric oxide synthase, cyclooxygenase-2, interleukin 1, and interleukin 6. Overall differences between groups and time periods and interactions thereof were calculated using a factorial analysis of variance (ANOVA).
  
  
  RESULTS
  The development of an interface membrane was noticed in both groups at both time points. However, in the controls the interface membrane regressed in thickness and biological activity, while both variables increased in the experimental group with the primary cement mantle defect over time. Nitric oxide (NO) and PGE2 concentrations were higher in the 8.5 months group (P < 0.0001) compared to the 2 months group with a tendency for the unstable group to have higher concentrations. The same was true for collagenolytic activity (P = 0.05), but not for caseinolytic activity that decreased over time (P < 0.0001).
  
  
  CONCLUSIONS
  In this study, a primary cement mantle defect of the femoral shaft elicited biomechanical instability and biochemical changes over time in an experimental animal study in sheep, that resembled the changes described at the bone cement-interface in aseptic loosening of total hip prosthesis in humans. The early biochemical changes may well explain the pathologic bone resorption and formation of an interface membrane as is observed in clinical cases. This animal model may aid in future studies aiming at prevention of aseptic loosening of hip prosthesis and reflect some aspects of the pathogenesis involved.
authors.affiliation: Musculoskeletal Research Unit, Dept of Veterinary Surgery, University of Zurich, Winterthurerstr, 260, 8057 Zurich, Switzerland. warrakel@uiuc.edu
authors.forename: Alexander O
authors.initials: AO
authors.lastname: El-Warrak
authors.forename: Marvin
authors.initials: M
authors.lastname: Olmstead
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schneider
authors.forename: Lorenz
authors.initials: L
authors.lastname: Meinel
authors.forename: Regula
authors.initials: R
authors.lastname: Bettschart-Wolfisberger
authors.forename: Margarete K
authors.initials: MK
authors.lastname: Akens
authors.forename: Joerg
authors.initials: J
authors.lastname: Auer
authors.forename: Brigitte
authors.initials: B
authors.lastname: von Rechenberg
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019644:Arthroplasty, Replacement, Hip; D001843:Bone Cements; D001862:Bone Resorption / Q000209:etiology; D015232:Dinoprostone / Q000032:analysis; D005260:Female; D005270:Femur Head / Q000737:chemistry*; D006622:Hip Prosthesis; D008566:Membranes / Q000737:chemistry; D045726:Metalloproteases / Q000032:analysis; D023421:Models, Animal; D009569:Nitric Oxide / Q000032:analysis; D016133:Polymerase Chain Reaction / Q000379:methods; D011475:Prosthesis Failure; D012756:Sheep; D014158:Transcription, Genetic
chemical_list: D001843:Bone Cements; D009569:Nitric Oxide; D045726:Metalloproteases; D015232:Dinoprostone