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Calcium phosphate materials are widely used as bone substitutes because of their properties close to those of the mineral phase of bones. Nevertheless, after several months, calcium phosphate-based materials release particles that may be phagocytosed by monocytes, leading to an inflammatory reaction. Strontium is well known to counteract the osteoporosis process, but little is known about its effect on inflammatory processes. The purpose of this work was to study the effect of biphasic calcium phosphate (BCP) particles substituted with strontium on the inflammatory reaction. Human primary monocytes stimulated or not by lipopolysaccharide (LPS) were exposed to BCP particles containing strontium for 6 and 24 h. Inflammatory mediators (cytokines and matrix metalloproteinases (MMPs)) production was then quantified by ELISA and zymography. We observed that the presence of strontium had few effects on unstimulated cells, but it decreased the production of pro-inflammatory cytokines and the chemokine interleukin 8 in LPS-stimulated cell-conditioned medium. This work suggests for the first time that strontium may be involved in the control of inflammatory processes following BCP phagocytosis by human monocytes., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Hydroxyapatite (HA) is widely used to coat metal parts in order to improve their biocompatibility. Analysis of retrieved tissues associated with failed implants, suggest that phagocytosis of HA wear debris by monocytes/macrophages might provide a potent stimulus for the release of a variety of cytokines. Phagocytosis involved a large variety of cellular receptors like toll-like receptors that results in activation of the transcriptional nuclear factor-kappaB (NF-kappaB) via a cell-signalling pathway. In the present paper, we aimed to evaluate the role of the toll-like receptor 4 (TLR4) in the production of inflammatory cytokines induced by HA particles using TLR4(+) and TLR4(-) peritoneal macrophages. We investigated the production of TNF-alpha and the activation of the nuclear transcription factor NF-kappaB. Our data clearly show for the first time that the production of TNF-alpha by macrophages exposed to HA particles was TLR4 dependent but not the activation of NF-kappaB. All these results open future therapies to reduce the inflammatory response induced by HA biomaterials.

A possible complication associated with the implantation of hydroxyapatite (HA)-based prosthesis is the release of particles. These particles can be phagocyted by monocytes that are among the first cells to colonize the inflammatory site. The activated monocytes produce inflammatory mediators such as cytokines that cause osteoclasts activation. The present work, describes studies on the effect of sol-gel derived zinc-substituted HA particles with various zinc substitution percentages (0.5-2%) on cytokine production (TNF-alpha, IL-1beta, IL-6, IL-10, and IL-8) by both LPS-stimulated or unstimulated human monocytes. Our data demonstrates that the zinc has an effect on cytokines production. It decreases the production of TNF-alpha and increases the production of IL-8 by unstimulated cells. Using LPS-stimulated cells, it decreases the production of inflammatory cytokines and increases the production of anti-inflammatory cytokine (IL-10), indicating that zinc-substituted hydroxyapatite has favourable effects on the cytokines production by monocytes.

A possible complication associated with the implantation of hydroxyapatite (HA)-based prosthesis is the release of particles. Those particles can be phagocyted by monocytes that are among the first cells to colonize the inflammatory site. The activated monocytes produce inflammatory mediators, such as cytokines, which cause osteoclasts activation. It has previously been demonstrated using a surface area ratio (ratio of the total surface of the given particles to the surface area of cells) of 1 to 1 that there was a correlation between the expression and production of cytokines induced by HA. The present work studies the effect of physical characteristics of HA particles on the production of various inflammatory cytokines (tumour necrosis factor-alpha, interleukin (IL)-6, and IL-8) and anti-inflammatory cytokine (IL-10). However, the experiments were performed using a surface area ratio of 10 to 1. Our data demonstrate that all the particles, whatever their characteristics, induced a high expression of cytokines but the production was different, meaning that there was a post-transcriptional regulation. The size and sintering temperature seemed to be a characteristics that were less important compared to the shape; the needle particles appeared to induce the most important production of all the cytokines studied.

Hydroxyapatite (HA) is widely used to coat the metal parts of prosthetic implants in order to improve their biocompatibility and as a bone defect filling material. HA has been demonstrated to produce particles at the prosthetic interface that lead to an activation of phagocytic cells that induce a cascade reaction leading to bone resorption and aseptic loosening. Monocytes/macrophages are commonly observed in the interface tissue, and are among the first cells to colonize the inflammatory site where they play a key role in the immune response. IL-18 is a pro-inflammatory cytokine. Monocytes/macrophages were described as IL-18 producing cells. IL-18 works antagonistically to IL-6, which activates osteoclastogenesis. In the present study, we investigated the ability of HA particles to induce the production of active IL-18 by human monocytes according to particle characteristics (size, sintering temperature and shape). Our study demonstrates, for the first time, that HA particles are capable of stimulating the production of the proinflammatory cytokine IL-18 in human monocytes according to their particle characteristics. The expression and the production of IL-18 was modified by the parameter studied. The difference observed between the expression and the production could be explain by the production of ICE. The needle shaped particles induced the larger production of IL-18.

After calcium-phosphates biomaterials based implantation like hydroxyapatite (HA) coating, particles are released in the periprosthetic tissues. Wear-debris induced fibrous membranes contain macrophage subsets that can produce metalloproteinases (MMPs), which are considered to be key enzymes in extra-cellular matrix turnover. Tissue inhibitors of metalloproteinases (TIMPs) are important regulator of MMPs activity. Interleukin-1 mainly produced by monocytes can also regulate MMPs production. In the present work, we have evaluated the effect of HA particles characteristics (size, shape and sintering temperature) on the MMP-2, -9 and their respective inhibitors TIMP-2, -1 production. Our results demonstrate that sintering temperature (that modify crystal size and surface area) have little effect on MMPs and TIMPs production. Non-phagocytable particles induced more MMP-9, although phagocytable particles induced more IL-1beta release. The shape of the particles was the most important factor since needle-shaped particles induced the most significant up-regulated expression of MMPs and IL-1beta.