Interaction of Materials and Biology in Total Joint Replacement - Successes, Challenges and Future Directions

Abstract

Total joint replacement (TJR) has revolutionized the treatment of end-stage arthritic disorders. This success is due, in large part, to a clear understanding of the important interaction between the artificial implant and the biology of the host. All surgical procedures in which implants are placed in the body evoke an initial inflammatory reaction, which generally subsides over several weeks. Thereafter, a series of homeostatic events occur leading to progressive integration of the implant within bone and the surrounding musculoskeletal tissues. The eventual outcome of the operation is dependent on the characteristics of the implant, the precision of the surgical technique and operative environment, and the biological milieu of the host. If these factors and events are not optimal, adverse events can occur such as the development of chronic inflammation, progressive bone loss due to increased production of degradation products from the implant (periprosthetic osteolysis), implant loosening or infection. These complications can lead to chronic pain and poor function of the joint reconstruction, and may necessitate revision surgery or removal of the prosthesis entirely. Recent advances in engineering, materials science, and the immunological aspects associated with orthopaedic implants have fostered intense research with the hope that joint replacements will last a lifetime, and facilitate pain-free, normal function.

Figure 1

Left: Pre-operative radiograph of a right hip with severe degenerative arthritis associated with hip dysplasia and impingement (arrow). Right: Post-operative radiograph with a modern, modular, porous coated, cementless metal-on-plastic total hip replacement.

Figure 2

Left: Pre-operative radiograph of a left total hip replacement with a cementless cup and a loose, cemented stem, which as migrated away from the cement mantle so that it is no longer centralized. The cement mantle has cracked and there is cement particle associated periprosthetic bone loss (osteolysis – arrows). Note the bowing of the femur due to remodeling. Right: Post-operative radiograph showing revision using a long-stem cementless femoral component. The femur was cut longitudinally to excise all of the cement and subsequently reduced and stabilized with wires (extended trochanteric femoral osteotomy).

Figure 3

Left: Pre-operative radiograph of a left hip with severe polyethylene wear of the acetabular component. Note that the femoral head is not centralized in the cup, indicating severe polyethylene wear. There is bone destruction in the acetabulum, and greater trochanter of the femur (arrows) due to the wear particle-induced inflammation. The cementless stem is well-fixed. Right: Post-operative radiograph showing revision of the entire acetabular cup and modular femoral head exchange, with bone grafting of the areas of osteolysis.

Figure 4

The balance between M1/M2 macrophages may influence the results of wear particle induced osteolysis. During wear particle induced chronic inflammation, infiltrated macrophages can recognize DAMP/PAMP/wear particles through TLRs. TLR activation enhances pro-inflammatory cytokine secretion including TNF-α, MCP-1, MIP1-α, IL-6, and IL-1β which leads to peri-prosthetic osteolysis. On the other hand, cytokines including IL-4, IL-10, or IL-13 can polarize macrophages into an M2 phenotype with anti-inflammatory functions. A decreased M1/M2 ratio of macrophages may therefore mitigate the osteolysis.

Figure 5

Metal-induced activation of innate and adaptive immune systems. (a) Total joint replacement derived metal wear debris can activate the innate immune system via several mechanisms. Protein coated wear particles of approximately micron size can activate macrophages and dendritic cells via recognition by TLRs and other PRRs. Metal ions activate innate immunity either indirectly by inducing cell necrosis and release of DAMP molecules, or in the case of cobalt ions, activating TLR4 signaling directly. TLR signaling induces dendritic cell maturation with increased expression of MHC-II and co-stimulatory molecules as well as cell migration to the local lymphatic tissue. At the same time macrophages and dendritic cells also phagocytose metal haptens, processing them along the endolysosomal route and finally presenting haptens on MHC-II molecule. (b) In lymphatic tissue, activated dendritic cells present metal haptens to the lymphocyte population. In genetically susceptible individuals, a subset of T lymphocytes recognize the neo-antigen with their T cell receptor and become activated assuming Th1-polarization and migrating back to the peri-implant tissues. (c) In peri-implant tissue immunocompetent Th1 cells recognize the macrophages that are presenting similar metal haptens and regulate their function by secreting such cytokines as IFN-γ. (d) IFN-γ secreted by the Th1 cells further enhances the metal-induced macrophage activation e.g. by increasing the expression of TLRs and the production of such pro-inflammatory factors as TNF-α and CCL2 that eventually lead to further macrophage recruitment and development of peri-implant bone loss.