The utilization of cobalt-chromium alloy (CoCr alloy) in joint prostheses as a bearing material is prevalent due to its exceptional anti-wear and anti-corrosive properties, which can be attributed to the presence of a protective oxide layer on its surface. However, during the service of a total hip prosthesis, especially of a prosthesis with metal-on-metal bearings or modular junctions, wear and corrosion of the alloy is an unavoidable problem, which releases metal wear particles and ions into the periprosthetic tissue [1,2]. And, after being phagocytosed by macrophages, the metal wear particles can also release ions in the acidified environment of the lysosomes [3,4].

In patients experiencing aseptic loosening of joint prostheses, wear particles consisting of CoCr, titanium, and polyethylene have been identified as significant contributors. Various research studies have demonstrated that wear particles can trigger inflammatory responses, stimulate M1 macrophage polarization, hinder osteogenic activity, and expedite osteoclast maturation, eventually resulting in bone resorption and aseptic loosening [5,6]. However, the impact of metal ions, such as Co(II) and Cr(III) ions, which are the products of corrosion in joint prostheses, on aseptic loosening has not been extensively explored.

Although Co and Cr are essential trace elements that participate in fundamental physiological processes, improper or over-dosed exposure to Co(II)/Cr(III) ions is related to hypersensitivity and intoxication [7]. Davda et al. reported a mean of 54 μM Co(II) and 151 μM Cr(III) of free ionic form in the periprosthetic fluid of revised metal-on-metal hip replacement [8]. Eltit et al. reported a mean of 82 μM Co(II) and 40 μM Cr(III) in the periprosthetic fluid of revised metal-on-polyethylene hip replacement [9]. The effects of locally accumulated Co(II)/Cr(III) ions on the periprosthetic bone and soft tissue are of significant clinical concern. The ions are thought to contribute to periprosthetic osteolysis and adverse local soft tissue reaction, the pathologic hallmarks of which mainly include massive macrophage infiltration and formation of lymphocyte aggregates [10], [11], [12].

However, limited by specimen availability, only the periprosthetic tissue of failed hip arthroplasty is available for analysis. The periprosthetic environment is a complex system influenced by multiple factors [5]. By analyzing the end-stage pathology of this multifactorial system, it's impracticable to determine the effects of Co(II)/Cr(III) ions and to judge the causative relation between ions exposure and the characteristic histologic manifestation.

To know what kind of effect, to what extent, and by what means Co(II)/Cr(III) ions contribute to the pathology of the artificial joint, well-designed in vitro and in vivo preclinical experiments are necessary. Although a few studies had investigated the effects of Co(II)/Cr(III) ions on the in vitro cultured cells [13], [14], [15], compared with culture media, the in vivo environment is much more complex. The presence of continuous fluid circulation, high buffer capacity, and complex cytokine regulation results in different effects for in vivo released Co(II)/Cr(III) ions. Moreover, the ions-protein complex produced in the in vivo setting is immunologically active [12,16]. However, few studies have focused on in vivo influence of Co(II)/Cr(III) ions on animals, particularly the effects on bone in the context of artificial joint replacement.

The challenge of studying in vivo effects of ions lies in how to continuously administering the ions to the bone at the same site. To address this problem, we set up a mouse model with a cavity on mouse calvaria to simulate the periprosthetic articular space using a 3D-printed helmet-like structure. Chronic interference was realized by repeatedly injecting the ion solutions into the cavity under the helmet. The objective of this study was to examine the effects of Co(II)/Cr(III) ions on mouse bone and the pathological alterations caused by ions exposure.