**3.2.1 Genetic background of tolerance to an implant**

324 Recent Advances in Arthroplasty

by an inner, secondary dense neocortex. There is bone ingrowth from the neocortex into the undulating surface of the cement mantle. This neocortex is connected to the outer, primary femoral cortex by new trabecular bone struts. These authors reported very little fibrous tissue intervening between the host bone and cement mantle around well-fixed implants (Jasty et al. 1990). They also suggest that loosening of the implant from the cement mantle (debonding) and fractures and fragments of the cement mantle coupled with ingrowth of a fibrous tissue layer between the implant surface and cement mantle may trigger loosening (*Part 2.3*). Based on this, *stable, intact and firm cement mantle together with adaptive physiological bone remodelling* 

A second mode of fixation is based on the use of special design features and surface technologies enabling bone interdigitating ingrowth to the porous surface of the implant (osteoconductive ingrowth surfaces). Biomaterials and coatings can modulate bone ingrowth. Finally, successful fixation of uncemented implants depends also on the

The initial fixation of the porous-coated implants to bone depends on the shape of the implant (e.g. wedge fit, threaded design), and/or the tight micromechanical locking (press fit, friction fit, scratch fit, interference fit) of an implant to the bone bed. *The initial stability of the cementless implant is considered to be important for the secondary stabilization via bone ingrowth*. The rough implant surface destined to fix the implant to bone has to come in contact with bone because bone cannot bridge very large gaps, perhaps exceeding 1-2 millimetres between the implant surface and bone. The micromotion at the bone-implant interface is first larger but diminishes below ~40 μm as bone grows to the surface of the implant. According to cadaver studies bone ingrowth can reach up to 50% in well-fixed implant while further penetration of the porous spaces available at the contact surface can reach 80%. These values vary according to the quality of bone, type of implant/surface

Also this process is dependent on bone remodelling, i.e. formation of bone multicellular units (BMU) undergoing activation-reversal-formation (ARF) cycles, with net production of new cortical and trabecular bone. It is not quite certain, what is the micromotion at the boneingrowth surface area preventing bone ingrowth. In simulated stair climbing micromotion of cementless implants it is up to 280 μm (Burke et al. 1991) which is close to 100-400 μm pore size commonly used in the porous coated implants still allowing bone ingrowth. The best implant-bone contact (bone ingrowth) is achieved in contact with compact, cortical bone characterized by Haversian channels. In other areas the porous surface may be in contact with ingrown cancellous, medullary bone without Haversian channels interdigitating rough implant surface. By this way the implant surface is connected with the

**3.2 Does it exist something like long-term tolerance to an implant? (Takakubo,** 

Assume that an experienced surgeon places well and firmly an appropriate implant. During a functioning of such THA soluble and insoluble particles of prosthetic biomaterials are deliberated from the prosthetic joint surfaces and the implant-bone interface has to withstand mechanical stresses on levels of multiple body weight. The question is on the mechanisms preventing premature destabilization of such implants. Although aseptic

**Pajarinen, Konttinen, Trebse, Coer, Mackiewicz, Takagi, Gallo)** 

*response* around are associated with a well fixed symptomless cemented implant.

**3.1.2 Physiological fixation of uncemented implants** 

technology, and zone of implant (Engh et al. 1995).

endosteal side of the cortex (Engh et al. 1995).

remodelling of already existing bone.

*Tolerance may be defined* as a state of progressively decreased responsiveness to a wear and corrosion particles as well as other stresses related to implant functioning. It is reasonable to hypothesize that the genetic background (host responsiveness) of the implant patient plays a role in loosening of or tolerance to the implant. Technically the approach taken has been to look for eventual single-nucleotide polymorphisms (SNPs) in candidate genes. SNP refers to single nucleotide base changes in the coding DNA at a particular site (natural sequence variants, alleles). Candidates for this approach have been sought among molecules, which according to the current understanding play a role in the pathomechanism of loosening. These candidates form three main classes, namely *molecules regulating bone metabolism* (influencing the fixation of an implant and maintenance of it), *proteinases* involved in collagenous tissue destruction (size of the effective joint space), and *chemokines/ cytokines* regulating inflammatory response to wear debris (aggressive granulomatosis). These processes are at least in part genetically regulated which opens theoretically the opportunity to screen the population preoperatively for risk patients. Current status in this field is described in *part 4.7*.

In sensitized individuals even low local metal ion concentrations, such as cobalt and chrome, can cause T lymphocyte-mediated, *delayed-type hypersensitivity (DTH) reactions*. Metal ions can bind to self-peptides in the antigen presenting groove of the major histocompatibility complex (MHC) class II molecule altering self to altered-self, which is by the adaptive immune response recognized as non-self. Metal ions can bind to a protein altering its processing so that immunogenic cryptic (instead of tolerance-inducing dominant) epitopes are disclosed, causing DTH. They can modify MHC-II making it an immune-incompatible, "a foreign tissue-type antigen" (like in rejection of allogenic transplants) or they can activate the T-cell a bit like superantigens do. Tolerance to implant would require also immune tolerance against hapteninduced hypersensitivity reactions and in special cases it might be possible to test the implant patient-to-be pre-operatively for an eventual hypersensitivity with the help of epicutaneous patch or gamma-spot like tests (*Part 4.5*).

In a tolerant immunogenetic background wear particles are together with apoptotic bodies cleaned by M0 macrophages. *Some co-factors* may interfere with this tolerant host response to implant. Biomechanical loading (compression, tension, shear force) at the implant-bone interface may be one such cofactor. Occasional infections, microbial pathogen-associated molecular structures (PAMPs, e.g. lipopolysaccharide) and release of alarmins (e.g. high mobility group box 1) from damaged tissues (e.g. excessive biomechanical loading or ischemia) and necrotic or even activated cells can transform the M0 macrophage response into aggressive granulomatosis, which leads to peri-implant bone destruction. This in part, because both PAMPs and alarmins can opsonize wear particles. Various pattern recognizing receptors, such as Toll-like receptors (TLRs), mediate innate host responses and their SNPs may play a role here (Takagi et al. 2007; Pajarinen et al. 2010). In addition, primary and longterm fixation of the cemented and uncemented implants is dependent on the remodelling ability of the bone which is under genetic control. Peri-implant cells have to resorb damaged or necrotic peri-implant bone, repair it and then remodel it so that it maintains implant well

Aseptic Loosening of Total Hip Arthroplasty as a Result of Local Failure of Tissue Homeostasis 327

areas around loosening implants (Takagi et al. 2001). This can expose cells in the 3D osteocytes-network to too high or low shear stress (drag force) leading to their apoptosis and aseptic necrosis. Osteocytes subjected to high pressures in peri-implant bone die a programmed cell death, apoptosis. Too low intracanalicular flow or obstruction of fluid inflow through surface pores by wear debris induces osteocyte apoptosis/bone necrosis. Taken together, patients should be strongly advised against extremely strenuous use of the implant to obtain good implant tolerance, but this is naturally also a patient and

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

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,

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

these new materials might facilitate development of implant tolerance.

ideal patient to maximize implant tolerance.

implant specific situation.

liners (Kurtz et al. 2011).

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

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, contributing to the osteolysis and loosening of an implant.

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

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, could protect the implant from excessive loads.

*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 areas around loosening implants (Takagi et al. 2001). This can expose cells in the 3D osteocytes-network to too high or low shear stress (drag force) leading to their apoptosis and aseptic necrosis. Osteocytes subjected to high pressures in peri-implant bone die a programmed cell death, apoptosis. Too low intracanalicular flow or obstruction of fluid inflow through surface pores by wear debris induces osteocyte apoptosis/bone necrosis. Taken together, patients should be strongly advised against extremely strenuous use of the implant to obtain good implant tolerance, but this is naturally also a patient and implant specific situation.
