Nano wear particles and the periprosthetic microenvironment in aseptic loosening induced osteolysis following joint arthroplasty

Abstract

Joint arthroplasty is an option for end-stage septic arthritis due to joint infection after effective control of infection. However, complications such as osteolysis and aseptic loosening can arise afterwards due to wear and tear caused by high joint activity after surgery, necessitating joint revision. Some studies on tissue pathology after prosthesis implantation have identified various cell populations involved in the process. However, these studies have often overlooked the complexity of the altered periprosthetic microenvironment, especially the role of nano wear particles in the etiology of osteolysis and aseptic loosening. To address this gap, we propose the concept of the "prosthetic microenvironment". In this perspective, we first summarize the histological changes in the periprosthetic tissue from prosthetic implantation to aseptic loosening, then analyze the cellular components in the periprosthetic microenvironment post prosthetic implantation. We further elucidate the interactions among cells within periprosthetic tissues, and display the impact of wear particles on the disturbed periprosthetic microenvironments. Moreover, we explore the origins of disease states arising from imbalances in the homeostasis of the periprosthetic microenvironment. The aim of this review is to summarize the role of relevant factors in the microenvironment of the periprosthetic tissues, in an attempt to contribute to the development of innovative treatments to manage this common complication of joint replacement surgery.

Keywords: aseptic loosening; homeostatic imbalance; joint arthroplasty; joint prothesis; microenvironment.

Figure 1

Structure of the artificial joint structure and sequential changes after prosthesis implantation. Artificial joint implantation for end-stage joint disease involves a process of removing damaged cartilage, synovial tissue, and osteophytes, followed by implanting a prosthesis composed of bone and artificial elements. The initial removal leads to joint tissue trauma and potential tissue necrosis, along with diminished synovial function. The body’s reparative processes subsequently get triggered, which involves phagocytosing necrotic tissue, forming woven bone, regrowing microvessels, and repairing synovial tissue, and increasing synovial fluid production. Over time, the prosthesis tightly integrates with the bone, although a decrease in bone density may occur post-implantation. Despite this, synovial function is ultimately restored, and the composition of synovial fluid in the artificial joint mirrors that of a normal one.

Figure 2

Cellular changes after joint implantation. During the initial phase of prosthesis implantation, neutrophils, as representatives of the acute inflammatory response, are the first to enter the cellular repair response at the site of injury, followed by macrophages and foreign body giant cells as representative cells of the chronic response in the prosthetic microenvironment. At the same time the repair of new capillaries and fibrous tissues gradually proceeds and eventually granulation tissue is formed.

Figure 3

Cell changes in periprosthetic environment after prosthesis implantation. (A): Inflammatory Response Post-Implantation (B): Bone Regeneration Post-Implantation (C): Synovial Repair Post-Implantation (D): Extracellular Matrix Post-Implantation The prosthetic microenvironment comprises cells and extracellular matrix, playing roles in inflammatory response, bone regeneration, and synovial repair. Cells like neutrophils, monocytes, eosinophils, mast cells, dendritic cells, and lymphocytes contribute to the inflammatory response. Neutrophils are the first to converge on the damaged area, eliminating DAMPs (necrotic cells and bone debris) via NETs (extracellular traps). Monocytes migrate to the prosthetic microenvironment, differentiating into macrophages to phagocytose necrotic cells, alongside tissue-resident macrophages. However, the exact mechanisms of eosinophils, mast cells, dendritic cells, and lymphocytes are not fully elucidated. During bone regeneration, mesenchymal stem cells differentiate into osteoblasts to stimulate osteogenesis. Osteoblasts subsequently encapsulated by bone form osteocytes, while osteoclasts are responsible for bone resorption. The synovial membrane consists of synovial-like and fibroblast-like cells, with macrophages aiding in its regeneration and endothelial cells participating in tissue repair. The extracellular matrix, largely studied in the context of wear particles, is an inevitable byproduct in the prosthetic microenvironment, dispersing within the synovial fluid and tissue areas of the joint.

Figure 4

Disruption of Microenvironment Homeostasis in Joint Prosthesis: Cellular and Extracellular Changes Leading to Aseptic Loosening. (A): Cellular Components Post-Implantation with homeostaisis (B): Extracellular Matrix Post-Implantation with homeostaisis (C): Changes in Cellular Components during Aseptic Loosening (D): Changes in Extracellular Matrix during Aseptic Loosening Following implantation, the microenvironment within the joint prosthesis initially attains stability. This is evidenced by the harmonious presence of diverse cell types, including osteoblasts, osteoclasts, osteocytes, synovial cells, and fibroblasts and the establishment of a steady extracellular matrix that includes the prosthesis, bone, and synovium. However, this state of balance is disrupted when aseptic loosening begins. This process initiates as wear particles trigger the differentiation of monocytes into macrophages. The macrophages that form from this differentiation process not only attract additional macrophages but also inhibit the differentiation of osteoblasts by releasing cytokines such as TNF-α. Concurrently, fibroblasts stimulate increased activity in osteoclasts via the RANKL-RANK axis. These changes lead to an overall increase in osteoclast activity and a suppression of osteogenesis. The response also includes participation from mast cells and dendritic cells. In addition, it is suggested that T lymphocytes participate in this process when metal wear particles are generated. The culmination of these alterations results in bone destruction, a roughened surface of the prosthesis, and an increase in synovial inflammation, all of which contribute to aseptic loosening.

Figure 5

The interaction between wear particles and macrophages in aseptic loosening. Wear particles of artificial joint prosthesis are often released into the prosthetic microenvironment because of overuse, Instability, and trauma factors. Monocytes can swallow wear particles, and when wear particles are swallowed by phagocytes, they will aggravate inflammation by releasing pro-inflammatory cytokines, chemokines, and M-CSF1 to activate M1 phenotype macrophages and promote the release of more inflammatory factors. Whereas osteoclast growth increases, causing increased osteolysis. Monocytes can also recognize stimulatory signals from wear particles through cell contact and release cytokines to further recruit more macrophages, while activating macrophages, causing more osteolysis. M2 phenotype macrophages and M1 phenotype macrophages can interconvert, with M2 phenotype anti-inflammatory macrophages phagocytosing wear particles to lyse and releasing cytokines to inhibit inflammation, as well as encapsulating granulomas to isolate inflammatory lesions.