**2.3 Comprehensive theory on aseptic loosening**

A valid theory requires consideration of *both mechanical and biological factors in the pathophysiology of aseptic loosening and osteolysis* (Gallo et al. 2002). The micromotions arising at the bone-implant interface during normal gait cycles induce a bone resorption which occurs before any wear debris particles enter the system. Following a number of "empty spaces" at the implant-bone interface are quickly filled by fibrous membrane. Repeated "compression" (stress) of the membrane during each step can induce proliferation of fibroblasts that synthesize an abundant extracellular matrix to adapt to the mechanical stresses and strains around an implant. According to this concept, the process of aseptic loosening is about *sequential hypertrophy of the interface membrane* (biological reaction to mechanical strain; Fig. 2). At a later stage, the hypertrophic membrane facilitates the delivery of particles, cytokines, enzymes and other molecules from the joint space to the bone bed interconnecting mechanical and biological factors.

The mechanical environment can induce differentiation of mesenchymal stem cells via up-, down-regulation of mechano-sensitive genes and in this way it can influence tissue differentiation resulting for instance in excessive formation of fibrous tissue (Aspenberg et al. 2000). Interestingly, macrophages can be activated by cyclic pressure (0.138 MPa) alone. In fact, there is significant increase in their expression of TNF-α, IL-1β and IL-6 when treated jointly with polyethylene particles and pressure (McEvoy et al. 2002). Other studies have demonstrate the relative sensitivity of macrophages to simultaneous application of PMMA particles and mechanical strain (Jones et al. 2006). With this in mind, one may conclude that mechanical conditions can directly regulate the proliferation and expression capacity of a particular cell group. Another scenario is based on evidence that *high-pressure waves of the synovial joint fluid* can induce bone necrosis (Fahlgren et al. 2010). An abundance of joint fluid is synthesized by synovial-like macrophages and fibroblasts inside the artificial joint as a response to inflammatory and secretory signals produced by particle disease. The degree of intraarticular pressure depends in part on the volume of joint fluid, changes in position of the joint, and volume/draining capacity of the joint space assuming that high-volume and effectively drained joint space are associated with lower intraarticular pressures and vice versa. Other factors that may be important, but are not readily analysed include at least interactions between implant and its surroundings in terms of local tissue homeostasis maintenance/distortion, favourable composition of joint fluid, type of lubrication, individual motion/stress pattern, and genetic predisposition to aseptic loosening.
