In 2011, approximately 1.6 million total hip arthroplasties (THAs) were conducted in 27 of the 34 member countries in the Organization for Economic Cooperation and Development (OECD) However, approximately 10–15% of patients still require revision surgery every year. Therefore, new technologies are required to increase the life-spam of the prosthesis from the current 10–15 years to at least 20–30 years. Our strategy focuses on surface modification of the bearing materials with a hydrophilic coating to improve their wear behaviour. These coatings are biocompatible, with high swelling capacity and antifouling properties, mimicking the properties of natural cartilage, i.e. wear resistance with permanent hydrated layer that prevents prosthesis damage. Clear beneficial advantages of this coating have been demonstrated in different conditions and different materials, such as UHMWPE, PEEK, CrCo, Stainless steel, ZTA and Alumina. Using routine tribological experiments, the wear for UHMWPE substrate was decreased by 75% against alumina, ZTA and stainless steel. For PEEK-CFR substrate coated, the amount of material lost against ZTA and CrCo was at least 40% lower. Further experiments on hip simulator adding abrasive particles (1-micron sized aluminium particles) during 3 million cycles, on a total of 6 million, showed a wear decreased of around 55% compared to uncoated UHMWPE and XLPE. In conclusion, CIDETEC‘s coating technology is versatile and can be adapted to protect and improve the tribological properties of different types of surfaces used for prosthesis, even in abrasive conditions.

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.

Summary. Understanding of the role of the radical-generating ability of wear particles of the existing and new implant materials as well as application of efficient antioxidants is one of the necessary conditions for improvement of the results of joint replacements. Introduction. Functioning of joint prostheses is accompanied by a continuous formation of wear particles and their accumulation in surrounding tissues. The impact of microroughnesses of joint prosthesis friction units may bring about chemical bond breakage and free-radical generation on a newly-formed wear surface. Wear particles of orthopedic alloys are capable to produce free radicals, and Co-Cr-Mo alloy particles are especially active. Free radicals generated by wear particles can cause oxidation and reduced wear resistance of polyethylene. Oxidised polyethylene particles stimulate the activity and release of bone-resorbing cytokines by human monocytes/macrophages. The ability of free radicals to cause damage to surrounding tissues and implant components makes it necessary to estimate comprehensively the radical-generating activity of wear particles of different orthopedic materials and develop the ways of its inhibition. Methods. Artificial Co-Cr-Mo alloy wear particles were obtained using dry friction of a ball against a disk. The radical-generating ability of orthopedic alloy wear particles was estimated by oxygen consumption using the model reaction of cumene oxidation. The radical-generating ability of wear particles was determined at different moments after their formation and storage at room temperature and humidity. In the experiments, a pro-inflammatory action of wear particles during their continuous formation was also simulated. Fresh cobalt alloy wear particles were used for a consecutive triple oxidation of 2 ml of cumene at a particle concentration of 0.3 mg/ml. After the first 40 min oxidation, a suspension of particles in cumene was centrifuged, and the used particles were removed. Fresh particles were added to oxidised cumene, and the second and third oxidations were carried out in a similar way. The ability of some antioxidants to inhibit the radical-generating ability of cobalt alloy wear particles was also determined. Results. Fresh cobalt alloy wear particles demonstrated an expressed radical-generating ability which remained practically at the initial level after a one-week storage. The ability gradually reduced in the process of storage. After a one-month storage the particles’ radical-generating ability decreased 2.6 times. A six-month storage of cobalt alloy particles resulted in a tenfold reduction of the radical-generating ability as compared to that of fresh particles. The intensification of radical formation was studied during three consecutive oxidations of cumene by wear particles. It was established that each consecutive oxidation of cumene by fresh wear particles occurred with a growing radical-generation ability. That parameter of the newly-formed particles increased more than two- and threefold during a consecutive double and triple cumene oxidation, respectively. Synthetic antioxidant BHT and natural antioxidant alpha-tocopherol were used for inhibition of wear particles-initiated free-radical reactions. Introduction of the antioxidants inhibited cumene oxidation with an antioxidant dose-dependent duration of this effect. In a mixture of alloy and orthopedic polyethylene particles, alpha-tocopherol completely inhibited the radical-generating activity of alloy particles thus preventing the polymer's oxidative destruction. Conclusion. The use of commercially available particles of orthopedic alloys with an uncontrolled duration storage in experiments considerably reduce or do not reveal the negative effects conditioned by their radical-generating ability. A proper study of the effect of the radical- generating ability of wear particles on the properties of implant components and surrounding tissues is possible only with the use of fresh particles. Permanent generation of free radicals in the process of wear of joint prosthesis metal components creates conditions for self-potentiation of negative free radical reactions during joint replacement. This requires the necessity of a preclinical estimation of the radical-generating ability of orthopedic materials and application of efficient antioxidants during the post-implantation period

Background. Aseptic loosening of prostheses is the most common cause for failure in total joint arthroplasty. Particulate wear debris induces a non-stop inflammatory-like response resulting in the formation of a layer of fibrous periprosthetic tissue at the bone/implant interface. The current treatment is an invasive revision joint replacement surgery. However, this procedure has a high morbidity rate, therefore, a less invasive alternative is necessary. One approach could be to re-establish osseointegration of the joint prosthesis by inducing osteoblast differentiation in the periprosthetic tissue. Therefore, the aim of this study was to investigate the capacity of periprosthetic tissue cells to differentiate into the osteoblast lineage. Methods. Periprosthetic tissue samples were collected during revision surgery of aseptic loosened hip prostheses, after which cells were isolated by collagenase digestion. Of 14 different donors, cells from passage 1 till 3 were used for differentiation experiments. During 21 days, cells were cultured under normal and several osteogenic culture conditions. Cultures were stained for alkaline phosphatase (ALP) activity and mineral deposits in the extracellular matrix. Results. When cells were cultured in osteogenic medium, ALP staining was increased compared to normal culture medium in 12 donors. Mineralisation of the matrix was observed in 13 donors. Addition of bone morphogenetic protein 2 or 6 (BMP) increased the ALP staining even further in 4 donors, whereas the mineralisation increased by 2–3 fold in 2 different donors. Nevertheless, in 1 donor, addition of a specific GSK3β inhibitor (GIN) to the osteogenic medium or a combination of both GIN and BMP2 was required to induce mineralisation of the matrix. Conclusions. Periprosthetic tissue cells show characteristics of differentiation into the osteoblast lineage when cultured under osteogenic conditions. However, the responses to different osteogenic stimuli were donor specific. Level of Evidence. Level IV. Experimental research study

Infection remains among the first reasons for failure of joint prosthesis. Currently, the golden standard for treating prosthetic joint infections (PJIs) is two-stage revision. However, two-stage procedures have been reported to be associated with higher costs and possible higher morbidity and mortality, compared to one-stage. Furthermore, recent studies showed the ability of a fast-resorbable, antibacterial-loaded hydrogel coating to reduce surgical site infections after joint replacement, by preventing bacterial colonization of implants. Aim of this study was then to compare the infection recurrence rate after a one-stage, cemenless exchange, performed with an antibacterial coated implant versus a standardized two-stage revision procedure. In this two-center prospective study, 22 patients, candidate to revision surgery for PJI, were enrolled to undergo a one-stage revision surgery with cementless implants, coated intra-operatively with a fast-resorbable, antibiotic-loaded hyaluronan and poly-D,L-lactide based hydrogel coating (“Defensive Antibacterial Coating”, DAC, Novagenit, Italy). DAC was reconstructed according to manufacturer indications and loaded with Vancomycin or Vancomycin + Meropenem, according to cultural examinations, and directly spread onto the implant before insertion. This prospective cohort was compared with a retrospective series of 22 consecutive patients, matched for age, sex, host type, site of surgery, that underwent a two stage procedure, using a preformed, antibiotic-loaded spacer (Tecres, Italy) and a cementless implant. The second surgery, for definitive implant placing, was performed only after CRP normalization and no clinical sign of infection. Clinical, laboratory and radiographic evaluation were performed at 3, 6 and 12 months, and every 6 months thereafter. Infection recurrence was defined by the presence of a sinus tract communicating with the joint, or at least two among the following criteria: clinical signs of infections; elevated CRP and ESR; elevated synovial fluid WBC count; elevated synovial fluid leukocyte esterase; a positive cultural examination from synovial fluid; radiographic signs of stem loosening. The two groups did not differ significantly for age, sex, host type and site of surgery (18 knees and 4 hips, respectively). The DAC hydrogel was loaded intra-operatively, according to cultural examination, with vancomycin (14 patients) or vancomycin and meropenem (8 cases). At a mean follow-up of 20.2 ± 6.3 months, 2 patients (9.1%) in the DAC group showed an infection recurrence, compared to 3 patients (13.6%) in the two-stage group. No adverse events associated with the use of DAC or radiographic loosening of the stem were observed at the latest follow-up months. This is the first report on one-stage cementless revision surgery for PJI, performed with a fast-resorbable antibacterial hydrogel coating. Our data, although in a limited series of patients and at a relatively short follow-up, show similar infection recurrence rate after one-stage exchange with cementless, coated implants, compared to two-stage revision. These findings warrant further studies in the possible applications of antibacterial coating technologies to treat implant-related infections

Summary. RNAi targeting p110β reduces TNF-alpha production and osteolysis in response to wear particles. Introduction. Aseptic joint loosening is a key factor that reduces the life span of joint prosthesis. Prosthetic wear particles are thought to play a central role in the initiation and development of periprosthetic osteolysis, leading to aseptic loosening of prostheses. This study aims to explore the effect of p110β-targeted small interfering RNA (siRNA) and lentivirus on particle-induced inflammatory cytokine expression in murine macrophage. Methods. siRNA and lentivirus targeting p110β were transfected and infected prior to particle stimulation, respectively. Ceramic and titanium particles of different sizes were prepared to stimulate macrophages. Fluorescence microscopy showed that the siRNA transfection and lentivirus infection efficiency were 74.2 ± 4.2% and 92.3 ± 2.6%, respectively. Results. Real-time polymerase chain reaction (PCR) showed that the levels of tumor necrosis factor-alpha (TNF-alpha) mRNA in the particle stimulation plus RNA interference (RNAi) groups were significantly lower compared with the particle stimulation-only groups (P<0.05), respectively. Similarly, enzyme-linked immunosorbent assay (ELISA) showed that protein levels of TNF-alpha in RNAi-treated groups were significantly decreased after transfection or infection (P<0.05), respectively. Western Blot showed that Phospho-Akt activation was significantly reduced by RNAi. As assessed by CT and micro-CT, particle implantation induced a significant osteolysis effect in mice calvaria, which was limited by p110β-lentivirus addition. Conclusions. p110β subtype of PI3K, followed by activation of phosphor-AKT (Ser473), may possibly participate in the regulation of activating macrophages by wear particles, ultimately resulting in the secretion of TNF-α and osteolysis

Summary. Osteoporosis reduces particle-induced osteolysis in rat model. Introduction. Wear particle induced osteolysis is considered to be a vital factor that reduces the life span of joint prosthesis. Osteoporosis is not rare in patients with indication for arthroplasty. However, the influence of osteoporosis on wear particles induced osteolysis is not clear. This study is aimed to explore on this issue by using animal model. Methods. 42 female Sprague-Dawley (SD) rats aged 6 months were randomly divided into 3 groups: A, B and C group. Group A and B contained 18 rats each, and group C contained 6 rats. The rats in group A underwent bilateral ovariectomy. Group B was normal control, and group C was sham control. After 3 months, 6 rats in group A, 6 rats in group B and all the rats of group C were sacrificed. Bone mineral density (BMD), μCT and bone histomorphometry were conducted. The rest of rats in group A were randomly divided into 2 groups: group A1 and group A2, and so were the rats in group B. 5mg titanium particles were implanted onto the calvaria of groups A1 and B1, and isometric PBS solution were injected to group A2 and B2. Calvaria were harvested after 14 days. Calvaria were analyzed by μCT and histomorphometry to measure the osteolysis area of calvarial sagittal suture. Results. Compared with B and C group, BMD and bone histomorphometry index of group A was significantly reduced (P<0.05), and tibial trabeculae of group A was slimmer. Area of calvarial sagittal suture osteolysis were 0.262±0.009mm. 2. , 0.130±0.013mm. 2. , 0.307±0.013mm. 2. and 0.178±0.011mm. 2. in A1, A2, B1and B2 groups, respectively. There was significant difference among the groups. Conclusions. Osteoporosis may reduce particle-induced osteolysis in rat model

Summary. RNAi targeting TNF-alpha inhibits particle-induced inflammation and osteolysis. Introduction. Over 1000,000 joint prostheses are implanted every year in the world. Aseptic joint loosening is a key factor that reduces the longevity of joint prosthesis. Prosthetic wear particles are thought to play a central role in the initiation and development of periprosthetic osteolysis, leading to aseptic loosening of prostheses. This study aims to investigate the effect of RNA interference (RNAi) targeting tumor necrosis factor-alpha (TNF-α) gene on particle-induced inflammation and osteolysis in macrophages in vitro and in vivo. Methods. An in vitro-transcribed small interfering (siRNA) sequences targeting mouse TNF-alpha gene from four candidates was screened and identified and then a lentivirus vector expressing short hairpin RNA (shRNA) was constructed to allow an efficient expression of TNF-alpha-siRNA. Lentivirus-mediated shRNA was transduced into mouse macrophages cells line RAW 264.7. Ceramic particles and titanium particles were added to stimulate cells 24 h after lentivirus transduction. TNF-alpha expression at both mRNA and protein levels were detected quantitatively by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) at different time intervals. Lentivirus-mediated shRNA suspension was locally administered into the murine calvarial model following local particle injection. Multi-slice spiral CT scan was used to evaluate the osteolysis of calvaria by detecting the width of the cranial sutures. Results. Lentivirus-mediated shRNA was effectively transfected, and inhibited the expression of TNF-alpha both in mRNA and protein level in RAW 264.7. Multi-slice spiral CT scan showed that lentivirus-mediated shRNA significantly suppressed osteolysis of mouse calvaria. Conclusion. Our investigation demonstrated that lentivirus-mediated shRNA targeting TNF-alpha gene could inhibit particle-induced inflammation and osteolysis in vitro and in vivo. Therefore, lentivirus-mediated gene therapy has the potential to be developed into a novel therapeutic strategy in the treatment of aseptic joint loosening

Summary Statement. We used three-dimensional software to assess different anatomic variables in the femur. The canal of Femur twisted slightly below the lesser trochanter in cases with a larger angle of anteversion. Introduction. Accurate positioning of the joint prosthesis is essential for successful total hip arthroplasty (THA). To aid in tailoring of the prosthesis, we used three-dimensional software to assess different anatomic variables in the femur. Patients & Methods. We used CT imaging data of the unaffected normal side of the 25 patients (22 females, age range 30 to 81 years) who underwent THA in 2012 in our hospital. The femur was reconstructed from CT data and measured using three-dimensional modeling software (Mimics 16.0 Materialise, Leuven, Belgium). We measured ellipse fitting to the medullary canal in the axial plane of the femur at 20-mm intervals. The angle between the major axis of those ellipses and the axis of the femoral neck was measured and expressed as the canal rotation. The distance between the lesser trochanter and the center of the femoral head was measured along the Z axis. Results. The major axes of the ellipses direct to medial, front and medial side in the level of epiphysis, above isthmus and distal portion respectively in all cases. The maximum rotated level was above isthmus. The rotation angle in the proximal portion ranged from 36 to 84 degrees (mean, 60.6 degrees, SD ± 12.1). The rotation angle of the distal portion ranged from 71 to 95 degrees (mean, 86.1 degrees, SD ± 6.1). Discussion/Conclusion. The torsion of the canal varied more widely between individuals in the proximal portion than did the distal portion. In addition, the torsion of the proximal aspect, although more variable, was on average smaller when the angle of anteversion was large. Because the canal twisted slightly below the lesser trochanter in cases with a larger angle of anteversion, it is suggested that attention to the degree of anteversion of a flat prosthesis stem is warranted

Summary Statement. An Implant Disposable Antibacterial Coating (i-DAC®) is described, consisting of a fully resorbable, biocompatible hydrogel, able to release antibacterial and antibiofilm agents. Direct application of the hydrogel on implants prevented infection occurrence in an in vitro model of peri-prosthetic infection. Introduction. Biofilm-related infections are among the main reasons for failure of joint prosthesis with high associated social and economical costs. Bacterial adhesion and subsequent biofilm formation have been shown to develop early after biomaterials implant into the human body, when a “race to the surface” takes place between the host's cells and the colonizing bacteria eventually present at the surgical site. Providing an antibacterial/antibiofilm coating of the implant may then play a strategic role in preventing biofilm related infections. Here we report the results of a series of in vitro and in vivo studies, partially performed under the European 7th Framework Programme (Implant Disposable Antibiotic Coating, IDAC, collaborative research project # 277988), concerning a fully resorbable, biocompatible antibacterial hydrogel coating (DAC®, Novagenit, Italy). The patented hydrogel, a co-polimer comprising of hyaluronic acid and a polylactic acid, has been designed to be mixed with various antibacterial agents and applied directly on the implant at the time of surgery, being fully resorbed within few days. Patients & Methods. The tested hydrogel (DAC®, Novagenit, Italy) is a derivative of a low molecular weight hyaluronan, grafted with poly-D, L-lactic acid and provided in powder form. At the point of care, the powder is hydrated with the antibiotic or antibiofilm solution, thus generating the final compound to be applied onto the implant surface. In vitro studies were conducted using DAC® coating on different biomaterials, including titanium, chrome-cobalt and polyethylene discs. The release of different antibacterial agents, including vancomycin, ciprofloxacin, meropenem, gentamycin, amikacin, tobramycin, clindamycin, doxycyclin, linezolid, NAsalycilate and N-acetylcisteine, adequately mixed with the hydrogel, has been tested by means of gas chromatography and microbiological methods. In vivo studies were then performed on 35 rabbits divided in 7 groups. Animals were implanted with an intramedullary titanium rod in their femur, with a known inoculum of methicillin-resistant Staph. aureus and vancomycin-loaded DAC® at different concentrations (2% and 5%) and compared with controls. Results. Regardless of the tested material, in vitro studies showed the ability of the hydrogel to be loaded and to sustain the release of the following antibacterial/antibiofilm compounds for up to 96 hours: vancomycin, ciprofloxacin, meropenem, gentamycin, amikacin, tobramycin, clindamycin, doxycyclin, linezolid, NAsalycilate, N-acetylcisteine. In vivo studies showed a bacterial load reduction ranging from 94% to 99.9% using vancomycin-loaded DAC®, compared to controls. Discussion/Conclusion. DAC®, a fast-resorbable antibacterial coating, showed the ability to be loaded with various antibacterial compounds and the ability to provide a highly significant reduction of bacterial colonization of implanted biomaterials in an animal model, opening a new pathway to local prevention and treatment of biofilm-/implant-related infections

We have designed a prospective study to evaluate the usefulness of prolonged incubation of cultures from sonicated orthopaedic implants. During the study period 124 implants from 113 patients were processed (22 osteosynthetic implants, 46 hip prostheses, 54 knee prostheses, and two shoulder prostheses). Of these, 70 patients had clinical infection; 32 had received antibiotics at least seven days before removal of the implant. A total of 54 patients had sonicated samples that produced positive cultures (including four patients without infection). All of them were positive in the first seven days of incubation. No differences were found regarding previous antibiotic treatment when analysing colony counts or days of incubation in the case of a positive result. In our experience, extending incubation of the samples to 14 days does not add more positive results for sonicated orthopaedic implants (hip and knee prosthesis and osteosynthesis implants) compared with a conventional seven-day incubation period.

Cite this article: Bone Joint J 2013;95-B:1001–6.