**3.1.1 Physiological fixation of cemented implants**

Cemented implants are fixed to bone with bone cement, polymethylmethacrylate (PMMA). Hip implant surgery damages descending metaphyseal arteries during the resection of the femoral head and the intramedullary nutritional artery during the implant bed preparation, which contribute to ischemia, lowering of pH and bone infarctions (Willert et al. 1974; Konttinen et al. 2001).

Willert and co-workers made a cadaver study of well-fixed implants to describe the physiological three-phase response of host bone to cement fixed implants. Toxic and lipolytic PMMA monomers and the exothermic polymerisation cause a marginal rim of necrosis of bone trabeculae at the cement-bone interface. After three weeks and up to two years postoperatively signs of repair of the implant bed are seen. This is perhaps in part stimulated by a local release of bone growth factors from the bone matrix and activated osteoclasts. Necrotic bone and bone fragments are resorbed by osteoclasts and macrophages. Newly produced or extended, irregularly orientated bone trabeculae grow as a laceworklike structure into the relatively smooth necrotic-fibrin clot-fatty-fibrotic bone-cement interface, which contains cement plugs, some of which protrude to reach direct contact with peri-implant bone. After two years bone repair is followed by remodelling of bone trabeculae, which are separated from the cement surface by a 0.1-1.5 mm thick fibrous membrane. This membrane grows into the empty spaces between the rough or cracked cement surface and contains some polyacrylamide pearls (from non-polymerized PMMA powder) close to the cement surface surrounded (isolated) by foreign-body giant cells and granulomas. Trabeculae of the already remodelled peri-implant bone were in the longitudinal sections orientated in parallel to the cement surface (Willert et al. 1974).

This work was nicely extended by Jasty and co-workers, who studied serial horizontal sections of the proximal femoral bone that enclosed the cemented femoral component still in place in the implant bed. They confirm that the bone is remodelled and disclose a curious pattern for this remodelling. The cement mantles of the well-fixed implants are surrounded

Aseptic Loosening of Total Hip Arthroplasty as a Result of Local Failure of Tissue Homeostasis 325

loosening and osteolysis are of multifactorial origin and many factors cannot be included into the failure analysis we believe that there is some place for a concept of host long-term tolerance to implant. Biological and non-biological circumstances (factors) can be associated

*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

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

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

with long-term painless and stable THAs.

described in *part 4.7*.

patch or gamma-spot like tests (*Part 4.5*).

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

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

### **3.1.2 Physiological fixation of uncemented implants**

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 remodelling of already existing bone.

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

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

#### **3.2 Does it exist something like long-term tolerance to an implant? (Takakubo, Pajarinen, Konttinen, Trebse, Coer, Mackiewicz, Takagi, Gallo)**

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 loosening and osteolysis are of multifactorial origin and many factors cannot be included into the failure analysis we believe that there is some place for a concept of host long-term tolerance to implant. Biological and non-biological circumstances (factors) can be associated with long-term painless and stable THAs.
