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J Am Acad Orthop Surg, Vol 16, No suppl_1, July 2008, S56-S62.
© 2008 the American Academy of Orthopaedic Surgeons
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What other biologic and mechanical factors might contribute to osteolysis?

Ed M. Greenfield, PhD and Joan Bechtold, PhD

Dr. Greenfield is Professor, Department of Orthopaedics, Case Western Reserve University, Cleveland, OH. Dr. Bechtold is Director of Research, Midwest Orthopaedic Research Foundation, and Associate Professor, Departments of Mechanical Engineering and Orthopaedic Surgery, University of Minnesota, Minneapolis, MN.

*The Implant Wear Symposium 2007 Biologic Work Group included Thomas W. Bauer, MD, PhD, Joan Bechtold, PhD, Mathias Bostrom, MD, Patricia A. Campbell, PhD, Victor Goldberg, MD, Stuart B. Goodman, MD, PhD, Ed M. Greenfield, PhD, Joshua J. Jacobs, MD, Yrjö Konttinen, MD, PhD, Regis O'Keefe, MD, PhD, Francis Young-In Lee, MD, Edward M. Schwarz, PhD, Arun S. Shanbhag, PhD, MBA, Robert Lane Smith, PhD, Rocky S. Tuan, PhD, and J. Mark Wilkinson, PhD, FRCS(Tr&Orth).

Dr. Bechtold or a member of her immediate family has received nonincome support (such as equipment or services), commercially derived honoraria, or other non-research–related funding (such as paid travel) from Material Transfer Agreement from Biomet, Inc. Neither Dr. Greenfield nor a member of his immediate family has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article.


   Abstract
Top
 Abstract
Endotoxins
 Implant Instability
 Future Directions for Research
 Figures
 Tables
 References
 
An overwhelming consensus exists that wear particles are the primary driving force in aseptic loosening of orthopaedic implants. Nonetheless, considerable evidence has emerged demonstrating that various other factors can modulate the biologic activity of orthopaedic wear particles. Two of the most studied modulating factors are bacterial endotoxins and implant motion. 


   Endotoxins
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 Endotoxins
Implant Instability
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The possibility that bacterial endotoxin contributes to aseptic loosening has received considerable attention recently.1-4 Lipopolysaccharide (LPS) is the classic endotoxin produced by gram-negative bacteria. However, both gram-negative and gram-positive bacteria produce many immunostimulatory molecules that have effects similar to those of LPS. These immunostimulatory molecules are collectively known as pathogen-associated molecular patterns (PAMPs). Many investigators have shown that LPS substantially increases the biologic activity of orthopaedic wear particles in cell culture and rodent models of aseptic loosening (Table 1), but the crucial question of whether PAMPs contribute to aseptic loosening in patients remains unanswered. Four types of evidence exist in support of this possibility.


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  		Table 1 Adherent Endotoxin Increases Biologic Activity of Orthopaedic Wear Particles
 
Sources of PAMPs in Patients With Aseptic Loosening
The most likely source of PAMPs in periprosthetic tissue is the bacterial biofilm that forms on implants in patients with aseptic loosening. Biofilms consist mainly of gram-positive bacteria.1-3,25 Studies employing microscopic, immunologic, and molecular biologic techniques have confirmed this and have shown that biofilms are more common than previously believed.26-30

A second source of PAMPs in a patient with aseptic loosening is accumulation from the patient’s circulation into the periprosthetic tissue. LPS exists in the circulatory system of people and animals31,32 and accumulates following implantation of endotoxin-free particles in both mice and rats.21,24 Whether PAMP accumulation contributes to osteolysis in the murine model is unknown. However, the longer time frame over which aseptic loosening occurs in patients provides an increased opportunity for PAMP accumulation to accelerate the process. Moreover, LPS accumulation inhibited osseointegration in one rat model.24

A third source of PAMPs in patients with aseptic loosening is bacterial debris on the implants themselves before surgical implantation. LPS has been detected on titanium disks prepared, sterilized, and packaged by a major orthopaedic manufacturer in the same manner in which the manufacturer handles commercial implants.33 LPS also has been detected on acetabular cups that had high failure rates due to impaired osseointegration.34 Cell culture studies suggest that PAMPs initially on implants may be more important in their ability to limit early osseointegration than for long-term osteolysis.35

Existence of PAMPs in Patients With Aseptic Loosening
LPS has been detected in periprosthetic tissue from a subset of patients with aseptic loosening.36 The frequency of LPS detection was much higher in patients with inflammatory arthritis than in those with osteoarthritis. It is unknown if the periprosthetic LPS is directly bound to the wear particles, but the LPS could increase the biologic activity of particles whether it is bound or not.

Peptidoglycan, a PAMP produced by both gram-negative and gram-positive bacteria, exists in synovial tissue from patients with both osteoarthritis and rheumatoid arthritis,37 and therefore likely exists in periprosthetic tissue, as well.

Macrophages in Periprosthetic Membranes of Patients With Aseptic Loosening Can Be Activated by PAMPs
Macrophages express high levels of a diverse array of PAMP receptors, including the Toll-like receptors and the nucleotide-binding oligomerization domain (NOD) proteins, and, as a result, are exquisitely responsive to the PAMPs.38 Moreover, macrophages in periprosthetic membranes express both PAMP receptors that were examined.39 Some PAMP receptors may also be activated by a variety of endogenous ligands.40,41 However, in many cases, this activation appears to be due to contamination of the endogenous ligand preparations with PAMPs or to interactions between PAMPs and the endogenous ligands.40,41 Thus, it is unclear whether PAMP receptors could contribute to aseptic loosening in the absence of PAMPs.

Antibiotics May Decrease Aseptic Loosening in Patients With Joint Arthroplasties
Long-term studies from the Norwegian Arthroplasty Registry indicate that combined local delivery of antibiotics in the bone cement with systemic administration of antibiotics can reduce the rate of aseptic loosening.42,43 Although this Registry includes a large number of patients, the Registry is not a randomized, controlled trial; thus, the result needs to be replicated. Moreover, it is unknown whether the decreased aseptic loosening is due to killing of bacteria by the antibiotics or to other effects of antibiotics, such as inhibition of metalloproteinases.

It is remarkable that short-term exposure to antibiotics would result in long-term reduction of aseptic loosening. The long-term antibiotic effectiveness may be due to inhibition of bacterial biofilm formation in the early postsurgical period. In the setting of both cementless and cemented implants, biofilm formation may provide a source of bacterial PAMPs that initiate a chronic low-grade inflammatory response, ultimately resulting in osteoclast upregulation and osteolysis. Prevention of biofilm formation with antibiotic therapy might explain the observed association with reduced aseptic loosening. In addition, another mechanism in cementless implants may be competition between the biofilm and the osteoblast to populate the implant surface. At sites where osteoblasts win this "race to the surface," bacterial exclusion might allow increased osseointegration.44,45 The long-term effectiveness of antibiotics may also be due to slow elution from the cement in vivo compared with the rapid elution observed in vitro.29,46


   Implant Instability
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 Abstract
 Endotoxins
 Implant Instability
Future Directions for Research
 Figures
 Tables
 References
 
Mechanical factors influence implant loosening. Previous studies have shown that the amount of motion (magnitude and interface strain), direction of motion (compression, shear, torsion), frequency of motion (high and low frequency), and rest periods all affect the tissue response to implants.

Relative motion between an implant and bone leads to the formation of a fibrous membrane.47,48 Such a membrane provides an environment within which other osteolytic stimuli become more potent. Several types of evidence support this premise. First, relative motion between implant and bone leads to formation of a fibrous membrane (Figure 1, A). Under controlled conditions of 500 µm of axial motion between experimental implants and the surrounding bone and with an interfacial gap of 0.75 mm, the implants consistently produce a loose connective-tissue fibrous membrane in the peri-implant space. This membrane persists for up to 16 weeks without change. The same result occurs with 120 µm of axial motion.48 Only in the case of a hydroxyapatite-coated implant does the motion-induced fibrous membrane convert to bone over time.49


Figure 1
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  		Figure 1 Tissue growth under unstable and stable interface conditions, with and without polyethylene (PE) particles (8 weeks). Diagram at top left shows a loaded unstable implant for applying a controlled axial movement of 500 µm to a cylinder of 6 mm diameter pistoning in a 0.75 mm circumferential bony gap in the canine knee during flexion and weight bearing. Particles of PE are injected into the gap. Diagram at top right shows a loaded stable implant without a spring. a = pistoning test implant, b = spring which ensures relative movement between the implant and bone, c = centralizing guide to constrain movement to axial direction. Bone trabeculae and thin fibrous membrane are seen for stable implants, both without (A) and with (B) PE. A fibrous membrane is consistently seen for unstable implants. Without PE (C), the membrane is loose connective tissue; with PE (D), the membrane is dense, with macrophages and high inflammatory cytokines. (Adapted with permission from Bechtold JE, Kubic V, Soballe K: Bone ingrowth in the presence of particulate polyethylene: Synergy between interface motion and particular polyethylene in periprosthetic tissue response. J Bone Joint Surg Br 2002;84:915-919.)

 
Second, the presence of polyethylene particles changes the features of the fibrous membrane (Figure 1, B). Under the same experimental conditions, adding polyethylene particles causes the membrane to become denser connective tissue, associated with higher inflammatory cytokines and lower transforming growth factor–beta (TGF-β) production.50,51 Furthermore, macrophages are recruited to the peri-implant space, where they ingest particles. A shell of bone at the original hole through which the implant is inserted is seen to become more complete.52

Third, polyethylene particles, when in an environment without relative implant-bone motion, do not prohibit bone growth (Figure 1, C and D). When the implant is stable (no relative motion at the implant-bone interface), bone consistently forms in the peri-implant gap. With the addition of polyethylene particles, bone growth still occurs, and bony spicules can be seen to surround the particles. Macrophages were not seen at a stable interface.50 These findings may be related to both the implant environment and to the particular particles (ie, some materials and shapes may be less well tolerated). Examples include decreased bone formation53 and increased inflammatory cytokines54 in an anchored (stable) bone harvest chamber in the presence of polyethylene particles (but not in the presence of diamond and SiC particles55). Also, ultra-high–molecular- weight polyethylene particles in a grossly stable setting (intramedullary pin in rat femur) were associated with an inflammatory response.56

Fourth, radiostereometric analysis studies suggest that early implant subsidence in bone is predictive of later loosening. Numerous clinical studies have shown that human femoral total hip arthroplasty implants with high early subsidence (relative motion) will later loosen clinically.57 This is consistent with the notion of early motion producing a fibrous membrane (before particles from wear are produced or before secure bony anchorage could occur). This finding reinforces the concept that favorable initial conditions (or a "race to the surface" where osteoblasts win) should be a goal for improving long-term results. Conditions that create a fibrous membrane (and greater migration and motion) are known to be associated with poorer clinical results.

Fifth, implant instability is associated with pumping of particles along the fibrous membrane. Particles may be transported along the fibrous membrane, which the particles cause to become more dense and inflammatory, through a pumping or a peristaltic motion. Only limited implant-bone pumping motion can occur if there is bony anchorage of the implant; likewise, if there is bony anchorage, no membrane forms to facilitate the process of particle transport.58,59 As a clinical example, femoral neck narrowing of metal-on-metal hip surface arthroplasties may be a manifestation of pressure-induced remodeling in the absence of excessive particulate debris.60

Sixth, fluid pressure (eg, joint fluid) can directly erode bone. Experimental studies with localized regions of high fluid pressure produced bony erosion in the absence of other factors. The addition of particles to pressure has been shown to exacerbate this effect (Table 2).


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  		Table 2 Experimental Models Investigating Pressure and Motion
 
Surface topography of the implant also affects tissue response. In the same implant model as that used in the studies discussed above, grit-blasted surfaces have lower interface strength than do plasma-sprayed surfaces, particularly in a setting in which a small gap exists between the implant and bone.64 When the implants are inserted press-fit, implant topography has a lesser effect. In selected treatments, nanotexture superimposed on a rough surface improves fixation.65-67 Other clinical factors influence the eventual performance of implant surfaces; for example, although rougher surfaces provide better initial fixation, they later loosen, providing more local wear.68

The evidence presented here is consistent with the premise that a fibrous membrane is necessary for creating an environment in which osteolysis can occur. In addition to mechanical consequences of motion and pressure in the initiation and maintenance of a fibrous membrane, biochemical factors that are associated with fibroblasts are associated with the osteolytic process. These data suggest that the presence of a fibrous membrane can potentiate other "noxious" factors.

Much of this work is based on animal models; limitations of these models require that the results be based in their intended context. Clearly, the clinical process of revision is a complex interplay of bone loss and defects, loss of structural support, impaired soft tissue, and reduced viability. These data provide control of some of the factors pertinent to the loosening process and can help direct specific therapies.


   Future Directions for Research
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 Abstract
 Endotoxins
 Implant Instability
 Future Directions for Research
Figures
 Tables
 References
 
An extremely promising approach to evaluate the role of PAMPs in aseptic loosening would be to determine whether polymorphisms in the genes encoding the PAMP receptors are associated with an increased risk of aseptic loosening. The feasibility of this approach has been demonstrated in studies showing that polymorphisms in cytokine genes are associated with the risk of aseptic loosening.69,70 Moreover, genome-wide analysis of polymorphisms can now be performed, which would allow identification of genes that might be associated with aseptic loosening in addition to PAMP receptors.

Additional scenarios regarding the role of mechanical factors should be considered. Whether implant motion necessarily precedes the formation of a fibrous membrane, or whether other conditions exist under which a fibrous membrane can be produced, is unknown. Furthermore, whether an initially secure bony anchorage can deteriorate and lead to late formation of a fibrous membrane to cause the appearance of particles in the implant-bone interface is unknown. However, bony anchorages have been shown to obstruct the transport of particles.58 Other factors, such as particle characteristics and amount, spatial distribution, and patient predisposition will influence whether osteolysis of clinical consequence results. These factors should be studied in conjunction with controlled mechanical factors (eg, motion and pressure).


   Figures
Top
 Abstract
 Endotoxins
 Implant Instability
 Future Directions for Research
 Figures
Tables
 References
 


   Tables
Top
 Abstract
 Endotoxins
 Implant Instability
 Future Directions for Research
 Figures
 Tables
References
 


   References
Top
 Abstract
 Endotoxins
 Implant Instability
 Future Directions for Research
 Figures
 Tables
 References
 

  1. Greenfield EM, Bi Y, Ragab AA, Goldberg VM, Nalepka JL, Seabold JM: Does endotoxin contribute to aseptic loosening of orthopaedic implants? J Biomed Mater Res B Appl Biomater 2005; 72:179-185.[Medline]
  2. Nelson CL, McLaren AC, McLaren SG, Johnson JJ, Smeltzer MS: Is aseptic loosening truly aseptic? Clin Orthop Relat Res 2005; 437:25-30. [Medline]
  3. Sundfeldt M, Carlsson L, Johansson C, Thomsen P, Gretzer C: Aseptic loosening, not only a question of wear: A review of different theories. Acta Orthop 2006; 77:177-197. [ISI][Medline]
  4. Neut D, van der Mei H, Bulstra S, Busscher H: The role of small-colony variants in failure to diagnose and treat biofilm infections in orthopedics. Acta Orthop 2007; 78:299-308.[ISI][Medline]
  5. Akisue T, Bauer TW, Farver CF, Mochida Y: The effect of particle wear debris on NFkappaB activation and pro-inflammatory cytokine release in differentiated THP-1 cells. J Biomed Mater Res 2002; 59:507-515.[ISI][Medline]
  6. Cho DR, Shanbhag AS, Hong CY, Baran GR, Goldring SR: The role of adsorbed endotoxin in particle-induced stimulation of cytokine release. J Orthop Res 2002; 20:704-713. [ISI][Medline]
  7. Bi Y, Seabold JM, Kaar SC, et al: Adherent endotoxin on orthopaedic wear particles stimulates cytokine production and osteoclast differentiation. J Bone Miner Res 2001; 16:2082-2091. [ISI][Medline]
  8. Bi Y, Collier TO, Goldberg VM, Anderson JM, Greenfield EM: Adherent endotoxin mediates biological responses of titanium particles without stimulating their phagocytosis. J Orthop Res 2002; 20:696-703. [ISI][Medline]
  9. Smith MV, Lee MJ, Islam AS, et al: The PI3K/Akt pathway mediates the biological response to titanium particles. J Bone Joint Surg Am 2007; 89:1019-1027. [Abstract/Free Full Text]
  10. Beidelschies MA, Greenfield EM: Adherent endotoxin increases activation of transcription factors by titanium particles. Trans Orthop Res Soc 2006;52:240.
  11. Hitchins VM, Merritt K: Decontaminating particles exposed to bacterial endotoxin (LPS). J Biomed Mater Res 1999; 46:434-437. [ISI][Medline]
  12. Carmody E, Schwarz E, O’Keefe RA: vIL-10 inhibits wear debris-induced cytokine production, osteoclastogenesis and bone resorption. Trans Orthop Res Soc 2002; 27:5.
  13. Brooks RA, Wimhurst JA, Rushton N: Endotoxin contamination of particles produces misleading inflammatory cytokine responses from macrophages in vitro. J Bone Joint Surg Br 2002; 84:295-299.[Medline]
  14. Daniels AU, Barnes FH, Charlebois SJ, Smith RA: Macrophage cytokine response to particles and lipopolysaccharide in vitro. J Biomed Mater Res 2000; 49:469-478. [ISI][Medline]
  15. Charlebois SJ, Daniels AU, Smith RA: Metabolic heat production as a measure of macrophage response to particles from orthopedic implant materials. J Biomed Mater Res 2002; 59: 166-175. [ISI][Medline]
  16. Schwab LP, Xing Z, Hasty HA, Smith RA: Titanium particles and surface-bound LPS activate different pathways in IC-21 macrophages. J Biomed Mater Res B Appl Biomater 2006; 79:66-73. [Medline]
  17. Lee DH, Park JC, Suh H: Synergistic induction of cyclooxygenase-II by bacterial lipopolysaccharide in combination with particles of medical device materials in a murine macrophage cell line J774A.1. J Biomed Mater Res 2001; 55:547-553. [ISI][Medline]
  18. Gordon A, Greenfield E, Kiss-Toth E, Eastell R, Wilkinson J: The role of endotoxin on pro-inflammatory cytokine mRNA expression in titanium stimulated macrophages. Trans Orthop Res Soc 2006;52:696.
  19. Skoglund B, Larsson L, Aspenberg PA: Bone-resorptive effects of endotoxin-contaminated high-density polyethylene particles spontaneously eliminated in vivo. J Bone Joint Surg Br 2002; 84:767-773.[Medline]
  20. Theiss SM, Luchetti W, Baker DG, Cuckler JM: The effect of endotoxin on the inflammatory response to particulate debris. Trans Orthop Res Soc 1993; 18:269.
  21. Tatro JM, Taki N, Islam AS, et al: The balance between endotoxin accumulation and clearance during particle-induced osteolysis in murine calvaria. J Orthop Res 2007; 25:361-369. [ISI][Medline]
  22. Taki N, Tatro JM, Nalepka JL, et al: Polyethylene and titanium particles induce osteolysis by similar, lymphocyte-independent, mechanisms. J Orthop Res 2005; 23:376-383. [ISI][Medline]
  23. Illgen R, Hotujec B, Bauer L, Forsythe T: The effect of endotoxin on the relative bioreactivity of conventional and highly crosslinked polyethylenes. Trans Orthop Res Soc 2007; 32:1792.
  24. Xing Z, Pabst M, Hasty K, Smith R: Accumulation of LPS by polyethylene particles decreases bone attachment to implants. J Orthop Res 2006; 24:959-966. [ISI][Medline]
  25. Trampuz A, Piper K, Jacobson M, et al: Sonication of removed hip and knee prostheses for diagnosis of infection. N Engl J Med 2007; 357:654-663. [Abstract/Free Full Text]
  26. Mariani BD, Martin DS, Levine MJ, Booth RE, Tuan RS: Polymerase chain reaction detection of bacterial infection in total knee arthroplasty. Clin Orthop Relat Res 1996; 331:11-22. [Medline]
  27. Tunney MM, Patrick S, Curran MD, et al: Detection of prosthetic joint biofilm infection using immunological and molecular techniques. Methods Enzymol 1999; 310:566-576. [ISI][Medline]
  28. Tunney MM, Patrick S, Curran MD, et al: Detection of prosthetic hip infection at revision arthroplasty by immunofluorescence microscopy and PCR amplification of the bacterial 16S rRNA gene. J Clin Microbiol 1999; 37:3281-3290. [Abstract/Free Full Text]
  29. Neut D, vanHorn JR, vanKooten TG, vanderMei HC, Busscher HJ: Detection of biomaterial-associated infections in orthopaedic joint implants. Clin Orthop Relat Res 2003; 413:261-268. [Medline]
  30. Dempsey KE, Riggio MP, Lennon A, et al: Identification of bacteria on the surface of clinically infected and non-infected prosthetic hip joints removed during revision arthroplasties by 16S rRNA gene sequencing and by microbiological culture. Arthritis Res Ther 2007; 9:R46. [Medline]
  31. Cooperstock MS, Tucker RP, Baublis JV: Possible pathogenic role of endotoxin in Reye’s Syndrome. Lancet 1975; 1:1272-1274. [ISI][Medline]
  32. Inada K, Endo S, Takahashi K, et al: Establishment of a new perchloric acid treatment method to allow determination of the total endotoxin content in human plasma by the limulus test and clinical application. Microbiol Immunol 1991; 35:303-314. [ISI][Medline]
  33. Ragab AA, VanDeMotter R, Lavish SA, et al: Measurement and removal of adherent endotoxin from titanium particles and implant surfaces. J Orthop Res 1999; 17:803-809. [ISI][Medline]
  34. Orthopaedic Device Forum Meeting Summation Report: http://www.orthopaedicdeviceforum.org/novsum03.htm . Accessed February 4, 2008.
  35. Nalepka J, Greenfield E: Adherent endotoxin inhibits attachment and proliferation of MC3T3-E1 pre-osteoblasts on titanium alloy substrates. Trans Orthop Res Soc 2006; 31:358.
  36. Nalepka JL, Lee MJ, Kraay MJ, et al: Lipopolysaccharide found in aseptic loosening patients with inflammatory arthritis. Clin Orthop Relat Res 2006; 451:229-235. [Medline]
  37. Schrijver IA, Melief MJ, Tak PP, Hazenberg MP, Laman JD: Antigen-presenting cells containing bacterial peptidoglycan in synovial tissues of rheumatoid arthritis patients coexpress costimulatory molecules and cytokines. Arthritis Rheum 2000; 43:2160-2168. [ISI][Medline]
  38. Lee MS, Kim YJ: Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu Rev Biochem 2007; 76:447-480. [ISI][Medline]
  39. Takagi M, Tamaki Y, Hasegawa H, et al: Toll-like receptors in the interface membrane around loosening total hip replacement implants. J Biomed Mater Res A 2007; 81:1017-1026.[Medline]
  40. Espehaug B, Engesaeter LB, Vollset SE, Havelin LI, Langeland N: Antibiotic prophylaxis in total hip arthroplasty. J Bone Joint Surg Br 1997; 79:590-595.[Medline]
  41. Engesaeter LB, Lie SA, Espehaug B, Furnes O, Vollset SE, Havelin LI: Antibiotic prophylaxis in total hip arthroplasty. Acta Orthop Scand 2003; 74:644-651. [ISI][Medline]
  42. Gristina AG: Biomaterial-centered infection: Microbial adhesion versus tissue integration. Science 1987; 237:1588-1595. [Abstract/Free Full Text]
  43. Gristina AG: Implant failure and the immuno-incompetent fibro-inflammatory zone. Clin Orthop Relat Res 1994; 298:106-118. [Medline]
  44. Neut D, van de Belt H, van Horn J, van der Mei H, Busscher H: Residual gentamicin-release from antibiotic-loaded polymethylmethacrylate beads after 5 years of implantation. Biomaterials 2003; 24:1829-1831. [ISI][Medline]
  45. Tsan MF, Gao B: Pathogen-associated molecular pattern contamination as putative endogenous ligands of Toll-like receptors. J Endotoxin Res 2007; 13:6-14. [Abstract/Free Full Text]
  46. Warger T, Hilf N, Rechtsteinner G, et al: Interaction of TLR2 and TLR4 ligands with the N-terminal domain of Gp96 amplifies innate and adaptive immune responses. J Biol Chem 2006; 281:22545-22553. [Abstract/Free Full Text]
  47. Bragdon CR, Jasty M, Greene M, Rubash HE, Harris WH: Biologic fixation of total hip implants: Insights gained from a series of canine studies. J Bone Joint Surg Am 2004; 86 (suppl 2):105-117. [Medline]
  48. Soballe K: Hydroxyapatite ceramic coating for bone implant fixation: Mechanical and histological studies in dogs. Acta Orthop Scand Suppl 1993; 1993:1-58.
  49. Soballe K, Hansen ES, Brockstedt-Rasmussen H, Bunger C: Hydroxyapatite coating converts fibrous tissue to bone around loaded implants. J Bone Joint Surg Br 1993; 75:270-278. [ISI][Medline]
  50. Bechtold JE, Kubic V, Soballe K: Bone ingrowth in the presence of particulate polyethylene: Synergy between interface motion and particulate polyethylene in periprosthetic tissue response. J Bone Joint Surg Br 2002; 84:915-919. [Medline]
  51. De Man FH, Tigchelaar W, Marti RK, Van Noorden CJ, Van der Vis HM: Effects of mechanical compression of a fibrous tissue interface on bone with or without high-density polyethylene particles in a rabbit model of prosthetic loosening. J Bone Joint Surg Am 2005; 87:1522-1533. [Abstract/Free Full Text]
  52. Bechtold JE, Kubic V, Soballe K: A controlled experimental model of revision implants: I. Development. Acta Orthop Scand 2001; 72:642-649. [ISI][Medline]
  53. Goodman SB, Ma T, Spanogle J, et al: Effects of a p38 MAP kinase inhibitor on bone ingrowth and tissue differentiation in rabbit chambers. J Biomed Mater Res A 2007; 81:310-316. [Medline]
  54. Trindade MC, Song Y, Aspenberg P, Smith RL, Goodman SB: Proinflammatory mediator release in response to particle challenge: Studies using the bone harvest chamber. J Biomed Mater Res 1999; 48:434-439. [ISI][Medline]
  55. Aspenberg P, Anttila A, Konttinen YT, et al: Benign response to particles of diamond and SiC: Bone chamber studies of new joint replacement coating materials in rabbits. Biomaterials 1996; 17:807-812. [ISI][Medline]
  56. Epstein NJ, Bragg WE, Ma T, Spanogle J, Smith RL, Goodman SB: UHMWPE wear debris upregulates mononuclear cell proinflammatory gene expression in a novel murine model of intramedullary particle disease. Acta Orthop 2005; 76:412-420. [ISI][Medline]
  57. Karrholm J, Herberts P, Hultmark P, Malchau H, Nivbrant B, Thanner J: Radiostereometry of hip prostheses: Review of methodology and clinical results. Clin Orthop Relat Res 1997; 344:94-110. [Medline]
  58. Rahbek O, Kold S, Bendix K, Overgaard S, Soballe K: Superior sealing effect of hydroxyapatite in porous-coated implants: Experimental studies on the migration of polyethylene particles around stable and unstable implants in dogs. Acta Orthop 2005; 76:375-385. [ISI][Medline]
  59. Rahbek O, Kold S, Zippor B, Overgaard S, Soballe K: Particle migration and gap healing around trabecular metal implants. Int Orthop 2005; 29:368-374. [ISI][Medline]
  60. Campbell P, Beaule PE, Ebramzadeh E, et al: The John Charnley Award: A study of implant failure in metal-on-metal surface arthroplasties. Clin Orthop Relat Res 2006; 453:35-46. [Medline]
  61. Skoglund B, Aspenberg P: PMMA particles and pressure: A study of the osteolytic properties of two agents proposed to cause prosthetic loosening. J Orthop Res 2003; 21:196-201. [ISI][Medline]
  62. McEvoy A, Jeyam M, Ferrier G, Evans CE, Andrew JG: Synergistic effect of particles and cyclic pressure on cytokine production in human monocyte/macrophages: Proposed role in periprosthetic osteolysis. Bone 2002; 30:171-177. [Medline]
  63. Skripitz R, Aspenberg P: Pressure-induced periprosthetic osteolysis: A rat model. J Orthop Res 2000; 18:481-484. [ISI][Medline]
  64. Overgaard S, Lind M, Rahbek O, Bunger C, Soballe K: Improved fixation of porous-coated versus grit-blasted surface texture of hydroxyapatite-coated implants in dogs. Acta Orthop Scand 1997; 68:337-343. [ISI][Medline]
  65. Meirelles L, Arvidsson A, Albrektsson T, Wennerberg A: Increased bone formation to unstable nano rough titanium implants. Clin Oral Implants Res 2007; 18:326-332. [ISI][Medline]
  66. Daugaard H, Elmengaard E, Bechtold J, Soballe K: Bone growth enhancement in vivo on press-fit titanium alloy implants with acid etched microtexture. J Biomed Mater Res A 2008 Jan 9 [Epub ahead of print]. [ISI][Medline]
  67. Biggs MJ, Richards RG, Gadegaard N, Wilkinson CD, Dalby MJ: Regulation of implant surface cell adhesion: Characterization and quantification of S-phase primary osteoblast adhesions on biomimetic nanoscale substrates. J Orthop Res 2007; 25:273-282. [ISI][Medline]
  68. Beksac B, Taveras NA, Valle AG, Salvati EA: Surface finish mechanics explain different clinical survivorship of cemented femoral stems for total hip arthroplasty. J Long Term Eff Med Implants 2006; 16:407-422. [Medline]
  69. Wilkinson JM, Wilson A, Stockley I, et al: Variation in the TNF gene promoter and risk of osteolysis after total hip arthroplasty. J Bone Miner Res 2003; 18:1995-2001. [ISI][Medline]
  70. Gordon A, Southam L, Loughlin J, et al: Variation in the secreted frizzled-related protein-3 gene and risk of osteolysis and heterotopic ossification after total hip arthroplasty. J Orthop Res 2007; 25:1665-1670. [Medline]




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