Stefan Landgraeber

Particle-Induced Osteolysis in Three-Dimensional Micro-Computed Tomography

Small-animal models are useful for the in vivo study of particle-induced osteolysis, the most frequent cause of aseptic loosening after total joint replacement. Microstructural changes associated with particle-induced osteolysis have been extensively explored using two-dimensional (2D) techniques. However, relatively little is known regarding the 3D dynamic microstructure of particle-induced osteolysis. Therefore, we tested micro-computed tomography (micro-CT) as a novel tool for 3D analysis of wear debris-mediated osteolysis in a small-animal model of particle-induced osteolysis. The murine calvarial model based on polyethylene particles was utilized in 14 C57BL/J6 mice randomly divided into two groups. Group 1 received sham surgery, and group 2 was treated with polyethylene particles. We performed 3D micro-CT analysis and histological assessment. Various bone morphometric parameters were assessed. Regression was used to examine the relation between the results achieved by the two methods. Micro-CT analysis provides a fully automated means to quantify bone destruction in a mouse model of particle-induced osteolysis. This method revealed that the osteolytic lesions in calvaria in the experimental group were affected irregularly compared to the rather even distribution of osteolysis in the control group. This is an observation which would have been missed if histomorphometric analysis only had been performed, leading to false assessment of the actual situation. These irregularities seen by micro-CT analysis provide new insight into individual bone changes which might otherwise be overlooked by histological analysis and can be used as baseline information on which future studies can be designed.

The Pathology of Orthopedic Implant Failure Is Mediated by Innate Immune System Cytokines

All of the over 1 million total joint replacements implanted in the US each year are expected to eventually fail after 15–25 years of use, due to slow progressive subtle inflammation at the bone implant interface. This inflammatory disease state is caused by implant debris acting, primarily, on innate immune cells, that is, macrophages. This slow progressive pathological bone loss or “aseptic loosening” is a potentially life-threatening condition due to the serious complications in older people (>75 yrs) of total joint replacement revision surgery. In some people implant debris (particles and ions from metals) can influence the adaptive immune system as well, giving rise to the concept of metal sensitivity. However, a consensus of studies agrees that the dominant form of this response is due to innate reactivity by macrophages to implant debris where both danger (DAMP) and pathogen (PAMP) signalling elicit cytokine-based inflammatory responses. This paper discusses implant debris induced release of the cytokines and chemokines due to activation of the innate (and the adaptive) immune system and the subsequent formation of osteolysis. Different mechanisms of implant-debris reactivity related to the innate immune system are detailed, for example, danger signalling (e.g., IL-1β, IL-18, IL-33, etc.), toll-like receptor activation (e.g., IL-6, TNF-α, etc.), apoptosis (e.g., caspases 3–9), bone catabolism (e.g., TRAP5b), and hypoxia responses (Hif1-α). Cytokine-based clinical and basic science studies are in progress to provide diagnosis and therapeutic intervention strategies.

Extrinsic and intrinsic pathways of apoptosis in aseptic loosening after total hip replacement.

Particle-induced osteolysis is a major cause of aseptic loosening after total joint replacement. The purpose of the current study was to identify various apoptosis-related pathways in the cellular response to wear debris. Fas receptor, BAK and caspase-3 cleaved were evaluated immunohistochemically in capsules and interface membranes from patients with aseptic hip implant loosening. Moreover, we investigated local cellular proliferation, documented by the presence of Ki-67, to evaluate the proportion of apoptosis in relation to the proliferation in the different cells. We detected a strong expression of caspase-3 cleaved, Fas and BAK in macrophages, giant cells and T-lymphocytes. The fibroblasts showed caspase-3 cleaved and BAK, but no Fas staining. Demonstrated by Ki-67 staining, we found increased proliferation of macrophages and fibroblasts. Statistical analysis showed a significant positive correlation (p<0.001) between the above mentioned results and the presence of wear debris. The intensity of apoptosis and proliferation differed, depending on the extent of osteolysis. Overall, four different patterns of immunoreactivity were identified. We think, however, that in particle-induced osteolysis apoptosis is pathologically increased - a phenomenon also seen in other diseases. In these instances, the number and degree of apoptotic reactions are so great that the resulting cell remains cannot be completely removed. This leads to an increased excretion of fibrogenic mediators that could be responsible for increased proliferation of fibroblasts in spite of the increased apoptosis. Moreover, it leads to an increased excretion of cytokines which could be responsible for the activation of osteoclasts.

Advanced core decompression, a new treatment option of avascular necrosis of the femoral head--a first follow-up.

Aseptic necrosis of the femoral head (AVN) leads to destruction of the affected hip joint, predominantly in younger patients. Advanced core decompression (ACD) is a new technique that may allow better removal of the necrotic tissue by using a new percutaneous expandable reamer. A further modification is the refilling of the drill hole and the defect with an injectable, hard‐setting, composite calcium sulphate (CaSO4)–calcium phosphate (CaPO4) bone graft substitute. Compression tests were performed on seven pairs of femoral cadaver bones. One femur of each pair was treated with ACD, while the opposite side remained untreated. Clinically, the postoperative outcome of 27 hips in 23 patients was performed by physical examination 6 weeks after ACD and at average follow‐up of 9.69 months, and compared with the preoperative results. MRI was used to assess the removal of the necrotic tissue, any possible progression of AVN and evaluation of collapse. In the biomechanical analysis, the applied maximum compression force that caused the fracture did not significantly differ from the untreated opposite side. The overall results of postoperative physical examinations were significantly better than preoperatively. Five hips (18.5%) were converted to a total hip replacement. The follow‐up MRIs of the other patients showed no progression of the necrotic area. The first follow‐up results of ACD have been encouraging for the early stages of aseptic necrosis of the femoral head. In our opinion, an assured advantage is the high stability of the femoral neck after ACD, which allows quick rehabilitation. Copyright

Measurement of the Silver Ion Concentration in Wound Fluids after Implantation of Silver-Coated Megaprostheses: Correlation with the Clinical Outcome

Background. Tumor patients and patients after traumas are endangered by a reduced immune defense, and a silver coating on their megaprostheses may reduce their risks of infection. The aim of this study was to determine the silver ion concentration directly measured from the periprosthetic tissue and the influence on the clinical outcome. Material and Methods. Silver ions were evaluated in 5 mL wound fluids two days postoperatively and in blood patients 7 and 14 days after surgery using inductively coupled plasma emission spectrometry in 18 patients who underwent total joint replacement with a silver-coated megaendoprosthesis. Results. The concentration of silver ions averaged 0.08 parts per million. Patients who showed an increased silver concentration in the blood postoperatively presented a lower silver concentration in the wound fluids and a delayed decrease in C-reactive protein levels. There were significantly fewer reinfections and shorter hospitalization in comparison with a group that did not receive a silver-coated megaprosthesis. Conclusion. An increased concentration of silver in the immediate surroundings of silver-coated prostheses was demonstrated for the first time in cohorts of patients with trauma or tumors. An elevated concentration of silver ions in the direct periprosthetic tissue may have reduced the infection rate.

Cobalt Alloy Implant Debris Induces Inflammation and Bone Loss Primarily through Danger Signaling, Not TLR4 Activation: Implications for DAMP-ening Implant Related Inflammation.

Cobalt alloy debris has been implicated as causative in the early failure of some designs of current total joint implants. The ability of implant debris to cause excessive inflammation via danger signaling (NLRP3 inflammasome) vs. pathogen associated pattern recognition receptors (e.g. Toll-like receptors; TLRs) remains controversial. Recently, specific non-conserved histidines on human TLR4 have been shown activated by cobalt and nickel ions in solution. However, whether this TLR activation is directly or indirectly an effect of metals or secondary endogenous alarmins (danger-associated molecular patterns, DAMPs) elicited by danger signaling, remains unknown and contentious. Our study indicates that in both a human macrophage cell line (THP-1) and primary human macrophages, as well as an in vivo murine model of inflammatory osteolysis, that Cobalt-alloy particle induced NLRP3 inflammasome danger signaling inflammatory responses were highly dominant relative to TLR4 activation, as measured respectively by IL-1β or TNF-α, IL-6, IL-10, tissue histology and quantitative bone loss measurement. Despite the lack of metal binding histidines H456 and H458 in murine TLR4, murine calvaria challenge with Cobalt alloy particles induced significant macrophage driven in vivo inflammation and bone loss inflammatory osteolysis, whereas LPS calvaria challenge alone did not. Additionally, no significant increase (p<0.05) in inflammation and inflammatory bone loss by LPS co-challenge with Cobalt vs. Cobalt alone was evident, even at high levels of LPS (i.e. levels commiserate with hematogenous levels in fatal sepsis, >500pg/mL). Therefore, not only do the results of this investigation support Cobalt alloy danger signaling induced inflammation, but under normal homeostasis low levels of hematogenous PAMPs (<2pg/mL) from Gram-negative bacteria, seem to have negligible contribution to the danger signaling responses elicited by Cobalt alloy metal implant debris. This suggests the unique nature of Cobalt alloy particle bioreactivity is strong enough to illicit danger signaling that secondarily activate concomitant TLR activation, and may in part explain Cobalt particulate associated inflammatory and toxicity-like reactions of specific orthopedic implants.

Comparison of subtraction arthrography, radionuclide arthrography and conventional plain radiography to assess loosening of total knee arthroplasty / Vergleich von Subtraktionsarthrographie, Radionuklidarthrographie und konventionellem Röntgen zur Erfassung von Prothesenlockerungen in der Knierevisionschirurgie

Abstract The value of plain radiographs, digital subtraction arthrography and radionuclide arthrography was analysed in 23 cases of failed total knee arthroplasty. The preoperative diagnosis was compared with the intraoperative assessment. Sensitivity, specificity and the positive and negative predictive value for assessing a loose component were determined separately for the femoral and tibial components. At revision we found 13 loose femoral and 12 loose tibial implants. In eight cases both components were unstable. Plain radiography had a sensitivity of 77% for loosening of the femoral and 83% for the tibial component; digital subtraction arthrography 77% for the femoral and 8% for the tibial component and radionuclide arthrography 31% and 8%. The specificity for plain radiography was 90% for the femoral and 72% for the tibial implant. For subtraction arthrography it was 50% and 82% and for subtraction arthrography 70% and 82%. Radiography had the highest positive and negative predictive values for both components compared with the other two techniques. As a diagnostic tool to detect implant loosening, plain radiography is the most effective in this study. Subtraction arthrography and radionuclide arthrography are not suitable for use as routine methods for detection of total knee arthroplasty loosening. In 23 Revisionen einer Kniegelenkstotalendoprothese wurden konventionelle Röntgenbilder, digitale Subtraktionsarthrographien und Radionuklidarthrographien analysiert, um die Effizienz dieser Methoden hinsichtlich der Diagnose von Implantatlockerungen festzustellen. Die präoperative Diagnose wurde mit dem intraoperativen Befund verglichen. Sensitivität, Spezifität und der positive und negative Vorhersagewert zu Erfassung einer Prothesenlockerung wurden separat für die femorale und tibiale Komponente erfasst. Bei der Revision wurden 13 gelockerte femorale und 12 gelockerte tibiale Implantate gefunden. In acht Fällen waren beide Komponenten gelockert. Konventionelles Röntgen hatte eine Sensitivität von 77% zur Erfassung einer Lockerung des femoralen Schilds bzw. 83% für die tibiale Komponente; die digitale Subtraktionsarthrographie ergab 77% für das femorale und 8% für das tibiale Implantat; die Radionuklidarthrographie hatte eine Sensitivität von 31% und 8%. Die Spezifität für konventionelles Röntgen lag bei 90% für femoral und 72% für tibial. Für die digitale Subtraktionsarthrographie waren es 50% und 82% und für die Radionuklidarthrographie 70% und 82%. Konventionelles Röntgen hatte den höchsten positiven und negativen Vorhersagewert für beide Komponenten verglichen mit den beiden anderen Techniken. Als diagnostisches Verfahren zur Erfassung einer Prothesenlockerung stellte sich das konventionelle Röntgen in dieser Studie als die effektivste Methode heraus. Die digitale Subtraktionsarthrographie bzw. die Radionuklidarthrographie eignen sich nicht als Routineverfahren zur Erfassung einer Kniegelenkstotalendoprothesenlockerung.

Functional interest of an articulating spacer in two-stage infected total knee arthroplasty revision

INTRODUCTION Deep periprosthetic infection is one of the most serious complications after total knee replacement. The two-stage procedure with implantation of a temporary cement spacer and later re-implantation of a revision total knee prosthesis is an accepted procedural standard. The use of articulating spacers has been proposed to enhance ease of revision and functional results. PATIENTS AND METHODS Twenty-three patients treated with an articulating spacer were retrospectively studied. All patients had undergone a two-stage surgery. The infected prosthesis was explanted and the femoral component was sterilized and re-implanted. On the tibial side a block of gentamicin-loaded bone cement was produced intraoperatively using specially manufactured templates. Eighteen total knee arthroplasty revisions and 5 arthrodesis were finally performed. RESULTS A total of three (13%) re-infections occurred 5-20 months after revision total knee arthroplasty in a mean follow-up period of 47 months. Prior to re-implantation, flexion with the articulating spacer ranged between 15 and 100° (mean 68±28°). The average postoperative flexion after re-implantation of total knee replacement was 105±11°. CONCLUSION The articulating spacer used in this study appears to be as effective as the standard procedures in terms of re-infection risk rate and postoperative range of motion recovery. LEVEL OF EVIDENCE Level IV.

Assessment and management of chronic pain in patients with stable total hip arthroplasty

Total hip arthroplasty (THA) is one of the most successful operations that can restore function and relieve pain. Although a majority of the patients achieve significant pain relief after THA, there are a number of patients that develop chronic pain for unknown reasons. A literature search was performed looking for chronic pain after total hip arthroplasty and stable THA. Major causes of chronic pain include aseptic loosening or infection. However, there is a subset of patients with a stable THA that present with chronic pain which can have several aetiologies. These include soft tissue, bony, neurological, vascular and psychological causes. Essential for successful treatment is the ability to make the correct diagnosis. Thus therapy may be either non-operative or operative. In addition, diagnosis and management often may require multidisciplinary approaches to successfully alleviate chronic pain in these patients with a stable prosthesis.

A prospective randomized peri- and post-operative comparison of the minimally invasive anterolateral approach versus the lateral approach

There is still controversy as to whether minimally invasive total hip arthroplasty enhances the postoperative outcome. The aim of this study was to compare the outcome of patients who underwent total hip replacement through an anterolateral minimally invasive (MIS) or a conventional lateral approach (CON). We performed a randomized, prospective study of 75 patients with primary hip arthritis, who underwent hip replacement through the MIS (n=36) or CON (n=39) approach. The Western Ontario and McMaster Universities Osteoarthritis Index and Harris Hip score (HHS) were evaluated at frequent intervals during the early postoperative follow-up period and then after 3.5 years. Pain sensations were recorded. Serological and radiological analyses were performed. In the MIS group the patients had smaller skin incisions and there was a significantly lower rate of patients with a positive Trendelenburg sign after six weeks postoperatively. After six weeks the HHS was 6.85 points higher in the MIS group (P=0.045). But calculating the mean difference between the baseline and the six weeks HHS we evaluated no significant differences. Blood loss was greater and the duration of surgery was longer in the MIS group. The other parameters, especially after the twelfth week, did not differ significantly. Radiographs showed the inclination of the acetabular component to be significantly higher in the MIS group, but on average it was within the same permitted tolerance range as in the CON group. Both approaches are adequate for hip replacement. Given the data, there appears to be no significant long term advantage to the MIS approach, as described in this study.