**3.2.3 The effect of gliding pairs, implants and fixation**

326 Recent Advances in Arthroplasty

fixed to the bone (*Part 3.1*). If fibrous interface and later synovial membrane-like interface or even foreign body-driven aggressive granulomatosus develop, activation-reversal-formation (ARF) cycles begin to dominate in bone multicellular units (BMUs) in peri-implant bone,

Our knowledge on the factors associated with long-term functioning of a stable implant is in part based on comparison of tissues from patients with long-term survival of implant with tissues from those who suffer from loosening. In this line, it was for instance proposed that *successful patients*, in contrast to unsuccessful ones, could *effectively clear the joint space from the wear and other particles* and this way have diminished inflammatory stimulation (Zolotarevova et al. 2010). Also other patient-related factors, like *gender, age, body mass index or even particular chronic medication* (e.g. statins, bisphosphonates, nonsteroidal antiinflammatory drugs) could contribute to implant tolerance (Thillemann et al. 2010a; Thillemann et al. 2010b). Female gender seems to protect both the cemented and uncemented cups from early failure (Roder et al. 2010). Tolerance to implant seems to be improved with increasing age of the patients which could be explained not only by a decrease in activity level with no excessive cyclic loading in elderly patients but also a decreased responsiveness of the immuneinflammatory system might play some role (Ogino et al. 2008). Normal body mass index contributes to good implant tolerance at least in part via influencing bone remodelling around the implant and magnitude of mechanical stresses affecting bone-implant interface. A good general health and medication not adversely interfering with bone metabolism together with a good local quality of the bone could contribute to long-term maintenance of implantbone fixation. In this line, it is advisable to check the health status and medication of particularly elderly patients to optimize bone metabolism and bone strength. Targeting the dizziness and an individualized training program (muscle strength, coordination, and balance) together with interventions to the physical living environment of the patient, e.g. carpets, handrails, bedrails, illumination, doorsteps and various technology-related aids,

*Implant fixation and loading* are interrelated and should be in balance for implant tolerance (*Part 3.1*). The number (cyclic regular loading) and type (on a smooth or declining surface, stairs, squatting etc.) of steps taken and any accidental or traumatic overshoots (not considered in computer controlled implant simulation studies) play a role. The number of steps taken can vary from 395 to 17718 steps per day, corresponding from 144175 to 6467070 steps per year (Schmalzried et al. 1998). In this way, it has been emphasized that the occurrence of polyethylene wear is a function of use, not time in situ (Schmalzried et al. 2000). Peri-implant bone microfractures and even pathological interface mobility can develop around already well-fixed implants as a result of too high loading. This secondary loss of stability stimulates bone remodeling (Takagi et al. 2001), and increases a risk for formation of fibrous interface around the implant. Fibrous tissue can further transform to synovial like-lining as a result of contact with synovial fluid (*Part 2.2*). Fibrous tissue formation is also promoted by the inert and passive nature of the metallic and polymeric materials used in joint replacements. Apart of the deteriorating effects of cyclic and erratic loading on development of fibrous interface, biomechanical loading affects also fluid flow and pressure in the lacuno-canalicular system. Detailed dynamic morphometric studies have shown high-turnover periprosthetic bone remodeling, immature bone formation and high density of osteocyte canaliculi in low-mineralized

contributing to the osteolysis and loosening of an implant.

could protect the implant from excessive loads.

**3.2.2 Other contributors to long-term tolerance of total hip arthroplasty** 

It is believed that the outcome of THA depends on optimal combination of patient, surgery and implant related factors. In this line, evidence-based implant surgery creates basic conditions for inducing an implant tolerance. Material and implant selections can also influence the conditions under which the tolerance to implant may develop. Regarding particle disease, key features are amount of particles together with their specific functional activity. Generally, ultra-high molecular weight polyethylene (UHMWPE) particles are considered more stimulating than ceramic particles. The amount of polyethylene wear debris has been significantly decreased by the development of highly cross-linked UHMWPE (HXLPE) even though concern on its specific functional activity remains. Wear rate was decreased by 50-95% by the 1st and 2nd generation HXLPE compared to conventional UHMWPE. As a result, the risk for osteolysis was diminished with 87% for the 1st generation of HXLPE liners compared to conventional UHMWPE liners (Kurtz et al. 2011).

In ceramic-on-ceramic (CoC) couples, with significant decrease of both the linear (5-300x) and the volumetric wear (30-2000x) in comparison to the metal on UHMWPE bearings (MoP), the risk for severe osteolysis is even lower. In metal on metal (MoM) articulations the linear wear is 5-150x less and the volumetric wear 30-1000 x less than in the conventional MoP (Jin et al 2006) but concerns remain regarding induction of both the delayed-type hypersensitivity, e.g. **A**septic **L**ymphocyte-dominated **V**asculitis-**A**ssociated **L**esions (ALVAL). Taken together, if indeed a particle disease plays a significant role in loosening, these new materials might facilitate development of implant tolerance.

Information on the effects of specific implant design on tolerance to implant is obtained from finite element modeling (FEM), simulation, case-control cohort and arthroplasty register studies. FEM, experimentation *in silica*, has been used for implant design and testing, implant biomechanics and implant-induced responses, e.g. bone remodeling and stress shielding, but few studies have applied FEM to estimate the longevity of different implant designs, i.e. the long-term tolerance to implants (Korhonen et al. 2005). Another method suitable for implant testing is computer-controlled simulation of real implants (Lappalainen et al. 2003). Randomized controlled clinical trials are the best way to evaluate specific implants in clinical practice. Unfortunately, they are rare. More frequent small and medium size observational cohort studies performed in a single center or geographical area can be biased. In that case, the most reliable information on the performance of different implants can be obtained using arthroplasty registers. Such registry studies also support the practice involving combination of antibiotics in the bone cement and systemically to decrease the risk of revision, i.e. improve implant tolerance (Engesaeter et al. 2003). Implant register studies can also be used to help to identify the ideal patient to maximize implant tolerance.

Aseptic Loosening of Total Hip Arthroplasty as a Result of Local Failure of Tissue Homeostasis 329

bacteria (Dempsey et al. 2007). In one recent study, it was even found that the extension of osteolysis correlated with proportion of positive sonication cultures (Sierra et al. 2011). Participation of the adaptive immune system in host response to prosthetic wear debris is still a subject of controversy despite the fact that several reports have described lymphocytes in periprosthetic tissues, retrieved from patients with aseptically failed metal-on-metal (MoM) or non-MoM implants (Fujishiro et al. 2011; Ng et al. 2011). One recent study revealed increased serum concentration of cobalt and chromium in patients with MoM THA which positively correlated with increased proportion of HLA DR+ CD8+ T-cells in these patients (Hailer et al. 2011). In the same study, it was proposed that macrophages around THA could create haptenic metal ions in the context of self peptides (metal ion-altered self) as antigens in combination with MHC class II molecules, leading to T-cell priming. Weyand et al proposed antigen-recognition events when they characterised T cells in periprosthetic membranes (Weyand et al. 1998). They found identical T-cell receptor sequences suggesting identical antigen specificity and in addition, transcription of IL-2 and IFN-γ, indicating functional activity of at least some lymphocytes. Moreover, in this study, IFN-γ transcription correlated with extension of bone loss. Sensitization to various heavy metals

**4.2 Chemokines and cellular chemotaxis during the inflammatory response to wear** 

The biological reaction to polymers, ceramics and metallic wear particles is *a non-specific foreign body and chronic inflammatory response*. A type IV lymphocyte-driven hypersensitivity reaction involving a specific antigen has been found for a small percentage of cases with predominantly metal-on-metal bearing surfaces (*Part 4.5*). This section will focus on the inflammatory processes associated with wear particles from orthopaedic implants, emphasizing local and systemic cell signaling mediated by chemotactic cytokines called

Resident macrophages are amongst the first cells involved in particle-associated inflammation and initiate cell recruitment via the release of chemokines. Macrophage activation may occur with or without phagocytosis, by cell membrane contact with particles (Goldstein et al. 1975). Several receptors in the outer membrane of macrophages (e.g. CD11b, CD14, Toll-like Receptors and others) are involved in the activation of macrophages after contact with particulate debris. These receptors act through transmembrane proteins and different intracellular pathways and result in the release of cytokines, chemokines and other substances that induce cell recruitment. One of the most important intracellular pathways involved in signal transduction is the *mitogen-activated protein kinase (MAP-Kinase) pathway*. The MAP-kinase pathway then activates transcription factors such as the Nuclear Factor Kappa B (NFB), which activates a cluster of genes for the production of pro-inflammatory cytokines, chemokines and related substances (Tuan et al. 2008). Besides macrophages, other resident cells are involved in the inflammatory process including fibroblasts, mesenchymal stem cells, osteoblasts, lymphocytes and others. Retrieval studies demonstrated that the periprosthetic cells produced high levels of pro-inflammatory cytokines and other factors including TNF, IL-1, IL-6, M-CSF,

after THA is described elsewhere in this chapter (*Part 4.5*).

**4.2.1 The inflammatory reaction to wear particles** 

chemokines.

RANKL, and others (*Part 4.3*).

**particles from orthopaedic implants** *(Gibon, Goodman, Gallo)* 
