Aims

This study intended to investigate the effect of vericiguat (VIT) on titanium rod osseointegration in aged rats with iron overload, and also explore the role of VIT in osteoblast and osteoclast differentiation.

Periprosthetic bone loss after total joint arthroplasty is a major clinical problem resulting in aseptic loosening of the implant. Among many cell types, osteoblasts play a crucial role in the development of peri-implant osteolysis. In this study, we tested the effects of calcitriol (1α,25-dihydroxy-vitamin-D. 3. ) and the bisphosphonate pamidronate on titanium-particle- and TNF-α-induced release of interleukin-6 and suppression of osteoblast-specific gene expressions in bone-marrow-derived stromal cells with an osteoblastic phenotype. We monitored the expression of procollagen α1[1], osteocalcin, osteonectin and alkaline phosphatase mRNAs by Northern blots and real-time reverse transcription and polymerase chain reaction analyses. The release of various cytokines was also analysed by ELISA. We found that calcitriol or pamidronate could only partially recover the altered functions of osteoblasts when added alone. Only a combination of these compounds restored all the tested functions of osteoblasts. The local delivery of these drugs may have therapeutic potential to prevent or to treat periprosthetic osteolysis and aseptic loosening of implants

Summary Statement. In vivo microCT allows monitoring of subtle bone structure changes around infected implants in a rat model. Introduction. The principal causes of orthopedic implant revisions are periprosthetic bone loss and infections. Immediately after implantation, a dynamic process of bone formation and resorption takes place around an orthopedic implant, influencing its mechanical fixation. Despite its importance, the effect of bacteria on the temporal pattern of periprosthetic remodeling is still unknown. The aim of this study was to evaluate the morphological changes of bone adjacent to an implant in the presence and absence of infection using micro computed tomography (microCT). Materials and methods. Twenty-four three-month-old female Wistar rats were used in this study. Twelve rats received a single control screw (sterile) in the proximal part of the right tibia while the other twelve received an infected screw (1×10. 4. CFU Staphylococcus aureus). The self-tapping cancellous bone screws, custom made of PEEK and coated with 30µm of titanium, were 2mm in outer diameter and 5mm in length. Bone changes around the screws were assessed using in vivo microCT with a nominal isotropic resolution of 12mm (at 70 kV, 300 ms integration time, 1000 projections) at days 0, 3, 6, 9, 14, 20 and 27. Each measurement took approximately 30 min while the animal was anesthetised via isoflurane inhalation. After reconstruction, these data were registered in space. The screw was segmented and dilated to define a region surrounding the coating. Bone-implant contact (BIC) was defined as the bone volume fraction (BV/TV) within this region. The changes in bone structure were computed from the differences between two consecutive time points. After sacrifice, in each group six tibiae were prepared for histology and six were used for mechanical pullout of the screw from the tibia, then quantitative microbiological analysis was carried-out after homogenization of the bone sample and sonication of the screw. Results. In the control group, no animal showed an infection, while all animals in the infected group developed an infection. In the uninfected group, BIC increased from 35±5% to 55±10% between day 0 and day 27 (p<0.05); at day 27 pullout stiffness was 220±48 N/mm and the maximal force 120±16 N. The microstructural changes were most prominent between day 0 and day 14. In the infected group, BIC dramatically dropped to zero within 14 days and the animals were sacrificed. Histology revealed that in the infected group there was marked osteolysis, purulent inflammation and a fibrous capsule around the screws. The pullout stiffness and maximal force were not significant (respectively 39±54 N/mm and 12±16 N). While 1×10. 4. CFU were introduced at day 0, at day 27, microbiological analysis revealed 1×10. 6. CFU on the screws and 5×10. 5. CFU in the neighboring bone. Conclusion. High-resolution in vivo microCT shows in the current model a rapid progression of osteolysis. This new approach allows a better understanding of the changes in bone structure around S. aureus infected implants. It may be particularly useful in detecting low-grade infections, such as S. epidermidis infections in the same model

Our aim was to determine whether in vitro studies would detect differences in the cellular response to wear particles of two titanium alloys commonly used in the manufacture of joint replacement prostheses. Particles were of the order of 1 μm in diameter representative of those found adjacent to failed prostheses. Exposure of human monocytes to titanium 6-aluminium 4- vanadium (TiAlV) at concentrations of 4 x 10. 7. particles/ml produced a mean prostaglandin E. 2. release of 2627.6 pM; this was significantly higher than the 317.4 pM induced by titanium 6-aluminium 7-niobium alloy (TiAlNb) particles (p = 0.006). Commercially-pure titanium particles induced a release of 347.8 pM. In addition, TiAlV stimulated significantly more release of the other cell mediators, interleukin-1, tumour necrosis factor and interleukin-6. At lower concentrations of particles there was less mediator release and less obvious differences between materials. None of the materials caused significant toxicity. The levels of inflammatory mediators released by phagocytic cells in response to wear particles may influence the amount of periprosthetic bone loss. Our findings have shown that in vitro studies can detect differences in cellular response induced by particles of similar titanium alloys in common clinical use, although in vivo studies have shown little difference. While in vitro studies should not be used as the only form of assessment, they must be considered when assessing the relative biocompatibility of different implant materials

Summary. Particulate wear debris with different chemical composition induced similar periprosthetic tissue reactions in patients with loosened uncemented and cemented titanium hip implants, which suggests that osteolysis can develop independent of particle composition. Introduction. Periprosthetic osteolysis is a serious long-term complication in total hip replacements (THR). Wear debris-induced inflammation is thought to be the main cause for periprosthetic bone loss and implant loosening. The aim of the present study was to compare the tissue reactions and wear debris characteristics in periprosthetic tissues from patients with failed uncemented (UC) and cemented (C) titanium alloy hip prostheses. We hypothesised that implant wear products around two different hip designs induced periprosthetic inflammation leading to osteolysis. Patients & Methods. Thirty THR-patients undergoing revision surgery were included: Fifteen patients had loose cemented titanium stems (Titan. ®. , DePuy) and 15 had well-fixed uncemented titanium stems (Profile, DePuy), but loose or worn uncemented metal-backed cups with conventional UHMWPE liners (Gemini, Tropic and Tri-Lock Plus, DePuy; Harris/Galante and Trilogy, Zimmer). A semi-quantitative histological evaluation was performed in 59 sections of periprosthetic tissues using light microscopy. Wear particles were counted by polarised light and high resolution dark-field microscopy. Additionally, particle composition was determined by SEM-EDXA following particle isolation using an enzymatic digestion method. Blood metal ions were determined with high resolution-ICP-MS. Results. The implants in the uncemented group were revised after a median of 15.7 years (range: 7.25–19.3) due to osteolysis and high wear of the polyethylene liner and metal backing resulting in gross metallosis, and/or cup loosening. The average lifetime of implants in the cemented group was only 6.5 years (range: 1.5–11.75) due to early stem loosening with large osteolysis pockets in the femur close to the cement mantle. Tissue examination revealed similar results for both groups: numerous mononuclear histiocytes and chronic inflammatory cells, a few neutrophils and multinucleated giant cells, and to some extent necrosis. The amount of metal particles per histiocyte positively correlated with the tissue reactions in the cemented, but not in the uncemented group. A higher particle load (medians: C: 14727 vs. UC: 1382 particles/mm. 2. , p<0.0001) was found in tissues adjacent to cemented stems, which contained mainly submicron ZrO. 2. particles. Particles containing pure Ti or Ti alloy elements (size range: 0.21 to 6.46 µm) were most abundant in tissues from the uncemented group. Here, also PE was more frequent, but accounted only for a small portion of total particles (2.8 PE/mm. 2. ). The blood concentrations of titanium (range: 3.8–138.5 microgram/L) and zirconium (cemented cases, range: 0.6–3.5 microgram/L) were highly elevated in cases with high abrasive wear and metallosis. Discussion/Conclusion. Phagocytosis of different wear particles by histiocytes induced a similar chronic inflammatory reaction in the periprosthetic tissues in both groups. ZrO. 2. particles, originating from bone cement degradation, dominated in the cemented group, while in the uncemented group the high abundance of pure Ti and Ti alloy particles of various sizes indicates wear of the metal-backed cups. The low density of polyethylene particles in the tissues suggests that they are not solely responsible for the tissue reactions and accompanying osteolysis. Our findings suggest that the chemical composition of wear particles plays a minor role in the mechanism of osteolysis. Particle size, load and ionic exposure might be more important

The effect of zoledronic acid on bone ingrowth was examined in an animal model in which porous tantalum implants were placed bilaterally within the ulnae of seven dogs. Zoledronic acid in saline was administered via a single post-operative intravenous injection at a dose of 0.1 mg/kg. The ulnae were harvested six weeks after surgery. Undecalcified transverse histological sections of the implant-bone interfaces were imaged with backscattered scanning electron microscopy and the percentage of available pore space that was filled with new bone was calculated. The mean extent of bone ingrowth was 6.6% for the control implants and 12.2% for the zoledronic acid-treated implants, an absolute difference of 5.6% (95% confidence interval, 1.2 to 10.1) and a relative difference of 85% which was statistically significant. Individual islands of new bone formation within the implant pores were similar in number in both groups but were 69% larger in the zoledronic acid-treated group. The bisphosphonate zoledronic acid should be further investigated for use in accelerating or enhancing the biological fixation of implants to bone.