Michiaki Takagi

Macrophages – Key Cells in the Response to Wear Debris from Joint Replacements

The generation of wear debris is an inevitable result of normal usage of joint replacements. Wear debris particles stimulate local and systemic biological reactions resulting in chronic inflammation, periprosthetic bone destruction, and eventually, implant loosening, and revision surgery. The latter may be indicated in up to 15% patients in the decade following the arthroplasty using conventional polyethylene. Macrophages play multiple roles in both inflammation and in maintaining tissue homeostasis. As sentinels of the innate immune system, they are central to the initiation of this inflammatory cascade, characterized by the release of proinflammatory and pro-osteoclastic factors. Similar to the response to pathogens, wear particles elicit a macrophage response, based on the unique properties of the cells belonging to this lineage, including sensing, chemotaxis, phagocytosis, and adaptive stimulation. The biological processes involved are complex, redundant, both local and systemic, and highly adaptive. Cells of the monocyte/macrophage lineage are implicated in this phenomenon, ultimately resulting in differentiation and activation of bone resorbing osteoclasts. Simultaneously, other distinct macrophage populations inhibit inflammation and protect the bone-implant interface from osteolysis. Here, the current knowledge about the physiology of monocyte/macrophage lineage cells is reviewed. In addition, the pattern and consequences of their interaction with wear debris and the recent developments in this field are presented.

Osteogenesis of human mesenchymal stem cells on micro-patterned surfaces:

Osteogenic responses of human mesenchymal stromal cells (hMSCs) were compared on square-patterned, inverse square-patterned, and planar titanium, chromium, diamond-like carbon (DLC), and tantalum; hypothesis was that both the materials and patterns affect osteogenesis. Samples were produced using photolithography and physical vapor deposition. Early-marker alkaline phosphatase (ALP) and mid-markers, small body size and mothers against decapentaplegic-related protein-1 (SMAD1), runt-related transcription factor-2 (RUNX2), and osteopontin were studied using quantitative real-time polymerase chain reaction. ALP and hydroxyapatite, were colorimetrically studied. ALP reached highest values on both patterned titanium samples, but mid-markers disclosed that it was already lagging behind planar and inverse patterned tantalum. Hydroxyapatite formation disclosed that osteo-induced hMSCs passed all the differentiation stages (except on planar chromium). Presence of hydroxyapatite disclosed that both types of patterning promoted (pu2009<u20090.001) osteogenesis compared to planar samples. Results suggest that the osseocompatibility/integration of implants could be improved by changing the monotonous and featureless implant–host interface into micro-patterned interface to provide physical differentiation cues.

Role and regulation of VEGF and its receptors 1 and 2 in the aseptic loosening of total hip implants

It was hypothesized that vascular endothelial growth factor (VEGF) in fibroblasts participates in aseptic loosening of total hip replacement (THR) implants. Therefore, osteoarthritic (OA) samples (nu2009=u200911) were compared with synovial membrane‐like interface tissues from revision THR (nu2009=u200910). VEGF‐A and its receptors were stained using streptavidin‐immunoperoxidase method. Their regulation by hypoxia and cytokines were studied in cultured fibroblasts using quantitative real‐time polymerase chain reaction (qRT‐PCR). VEGFR1+ lining cells (pu2009<u20090.01), stromal fibroblast‐like cells (pu2009=u20090.001) and stromal macrophage‐like cells (pu2009<u20090.05) were more numerous in rTHR than in OA. As to VEGFR2+, only stromal fibroblast‐like cells in rTHR outnumbered those found in OA (pu2009<u20090.05). VEGFRs in synovial fibroblasts were not affected by hypoxia, but VEGF increased 2.4‐fold (pu2009<u20090.05). Interleukin‐4 up‐regulated VEGFR1 expression 23‐fold. This is the first study to describe a difference between rTHR and OA in VEGF receptors, particularly VEGFR1. Hypoxia increased VEGF, but the VEGFR1 increase in the lining and stroma is probably IL‐4 driven, in accordance with the M2‐type macrophage dominance in interface tissues. VEGF/VEGFR system is also affected by hypoxia and may play a role in angiogenesis and bone pathology in aseptic loosening of total hip implants.

Inflammatory immune cell responses and Toll-like receptor expression in synovial tissues in rheumatoid arthritis patients treated with biologics or DMARDs

Biologic antirheumatic drugs (BIO) have been reported to be potent therapeutic agents in the prevention of inflammatory joint destruction in rheumatoid arthritis (RA). The aim of this study was to investigate the immune-inflammatory cells, including Toll-like receptor (TLR)-equipped cells, in synovial tissue samples from RA patients on BIO compared to patients, who are only on conventional disease-modifying antirheumatic drug (DMARD). We analyzed immune-inflammatory cells in RA synovitis in patients of BIO group (nu2009=u200920) or DMARD group (nu2009=u200920). The grading scores of synovitis was 1.7 and 1.8 in each BIO and DMARD group and correlated best with the CD3+ T (ru2009=u20090.71/0.70, pu2009<u20090.05) and CD20+ B (ru2009=u20090.80/0.84, pu2009<u20090.05) cells in the both groups, but less well with the CD68+ macrophages and S-100+ dendritic cells (DCs). Interestingly, both T (116 vs. 242, pu2009<u20090.05) and B (80 vs. 142, pu2009<u20090.05) cell counts were lower in the BIO than in the DMARD group, whereas macrophage and DC counts did not differ. In contrast, the C-reactive protein (CRP) and disease activity score DAS28-CRP did not show clear-cut correlations with the inflammatory grade of the synovitis (r range, 0–0.35). Similar numbers of cells immunoreactive for TLR-1 to TLR-6 and TLR-9 were found in synovitis in both groups. Patients clinically responding to biologics might still have the potential of moderate/severe local joint inflammation, composed in particular of and possibly driven by the autoinflammatory TLR+ cells.

Aseptic Loosening of Total Hip Arthroplasty as a Result of Local Failure of Tissue Homeostasis

Total hip arthoplasty (THA) is the most effective and safest method for treating severe degenerative, post-traumatic and other diseases of the hip joint. It is estimated that more than 1,000,000 THAs are performed each year globally. The incidence of primary THA increased in the period 1990 to 2002 in the USA from 47/100,000 to 69/100,000 (Kurtz et al. 2007). A similar study in Denmark reported an increased rate of THAs from 101/100,000 to 131/100,000 during the period 1996 to 2002 (Pedersen et al. 2005). More importantly, modelled future projections expect further increase in the need for THAs. It is believed that THA can reliably relieve pain and improve function in the majority of patients for a period of 15 to 20 years or more postoperatively. On this basis, with the extension of THAs to a younger and generally more active population, the expected time of service of THAs would be insufficient and the number of revision surgeries would therefore increase during this time. The Kaplan-Meier ten-year revision-free survival estimates for younger patients range from 72% (95%CI: 67-76) in Finland to 86% (95%CI: 84,5-88,2) in Sweden (Corbett et al. 2010). Hence, 14% to 28% of such patients on average did not achieve a 10-year THA functioning without revision. The main reason for late failure of THA is aseptic loosening accompanied by osteolysis followed by infection and instability of the THA that compromise more the early postoperative

Materials used for hip and knee implants

Abstract: The biomaterials used in hip and knee implants aim to maximise beneficial mechanical properties (e.g. wear resistance and fatigue strength), minimise material deterioration (e.g. corrosion and degradation) and enable the long-term integration of the implant into the musculoskeletal system. The major aim is to optimise the rate and quality of bone apposition and minimise the rate of wear, corrosion or other degradation products and the adverse tissue responses to them. This chapter discusses the evolution of materials used in hip and knee implants and the internal/surface treatments used to improve the properties of the implants.

Midterm clinico-radiologic findings of an open label observation study of add-on tacrolimus with biologics or non-biologic DMARDs

Tacrolimus (TAC) suppresses immune-inflammation by an intermediary inhibition of calcineurin activation in the treatment of rheumatoid arthritis (RA). Various combination therapies for RA have been reported to be superior to monotherapies. The aim was therefore to study add-on TAC in a combination with biologics (BIO) and/or non-BIO disease-modifying anti-rheumatic drugs (DMARDs) in treatment-resistant patients. In eight RA patients, TAC was added on to BIO (TAC/BIO group) and in forty-one to non-BIO DMARDs (TAC/non-BIO group). The mean C-reactive protein (CRP) decreased from 33xa0mg/l at the baseline to 16xa0mg/l at first year in the TAC/BIO group (Pxa0<xa00.05), from 41 to 14xa0mg/l in the TAC/non-BIO group (Pxa0<xa00.05); the mean DAS28-CRP (28 joint count) disease activity score decreased from 5.3 to 4.4 in the TAC/BIO group (Pxa0<xa00.05) and from 5.0 to 3.9 in the TAC/non-BIO group (Pxa0<xa00.05). The median of Δ modified total Sharp score decreased from 43 during the year preceding the baseline to 3 during the first year of the follow-up in the TAC/BIO group (Pxa0<xa00.05) and from 22 to 0 during the second year in the TAC/non-BIO group (Pxa0<xa00.05). Twenty-six adverse events occurred in this study in 26 patients (53% in all); however, the only severe adverse event was one case of an atypical mycobacterial disease (2%). The combination therapy of TAC with BIO or non-BIO DMARDs represents an effective and relatively safe mode of therapy in treatment-resistant RA.

Biomaterial–Host Interactions in Aseptic and Septic Conditions

Implanted total joint replacement is initially osteointegrated via successive steps of inflammation, resorption of necrotic bone, bone matrix production and ultimately bone remodeling, and is largely mediated by the coordinated action of osteoclasts and osteoblasts. Years later, a total joint replacement that has previously been well osteointergrated, can become loosened necessitating technically difficult and costly revision operations. Two different modes of prosthesis loosening have traditionally been distinguished, namely prosthesis infection, also known as septic loosening, and aseptic prosthesis loosening. Septic and aseptic prosthesis loosening have long been considered as two separate entities where septic loosening is due to chronic inflammation and accompanied osteolysis caused by bacterial infection of prosthesis components while aseptic loosening is driven by macrophages inflammatory foreign body reaction against biomaterial wear particles that are generated due to unavoidable abrasion between prosthesis components. During last decade this strict dichotomy between septic and aseptic prosthesis loosening has been questioned by observations that subclinical bacterial biofilms are present at last in some cases of aseptic prosthesis loosening and that the pro-inflammatory and osteolytic properties of wear particles are largely dependent on the presence of bacterial structural components adhering to their surfaces. The recognition of such bacterial product coated wear particles and subsequent activation of macrophages to inflammatory phenotype is possibly mediated by Toll-like receptors expressed in the interface tissues. Further studies are warranted to better characterize the role of subclinical bacterial biofilms in the aseptic prosthesis loosening. Peri-implant B lymphocyte and plasma cell infiltrates might provide additional diagnostic tools to detect such, low-grade, biofilm hidden implant infections.