Total Joint Replacement Surgery Research Articles

Development of a Sequential Antibiotic Releasing System for Two-Stage Total Joint Replacement Surgery.

In recent years, there has been an increase in nanoparticle research towards creating better release systems that can maintains the effective dosage over desired periods. Conventional nanoparticle systems have not been successful for this goal. Thus, the aim of this study is to evaluate the sequential release profiles of hybrid materials, combining nanoparticles, hydrogels and bone cement, for the treatment of arthroplasty infections. In this study, Vancomycin, which is one of the most used antibiotics in orthopedics, was loaded to alginate-chitosan nanoparticles. These drug-loaded nanoparticles were dispersed in an alginate gel and the gel covered the polymethylmethacrylate bone cement. After the crosslinking of the gel around the bone cement, the sequential release profile was evaluated for 60 days in vitro. The results of the morphological, chemical characterization and encapsulations studies showed that different loadings of drugs resulted in different encapsulation efficiencies. Although the release profile from the nanoparticles was as expected, the sequential release profile of the combined system has a Fickian type release for a longer time period. In conclusion, the results indicate that combining different release systems can alter the release profile of the system.

1100. Facility Factors Are a Stronger Driver of Peri-Operative Vancomycin Use Than Patient Risk Factors

BackgroundPrior reports suggest that the use of vancomycin for surgical prophylaxis is common and increasing. However, rates of administration and reasons for choosing vancomycin are unknown. Thus, we sought to quantify the frequency of vancomycin as a surgical prophylaxis agent and to determine drivers of use.MethodsAll Veteran patients undergoing major cardiac, orthopedic total joint, vascular, or colorectal procedures and entered into the VA External Peer Review Program (EPRP) database during the period from October 1, 2008 to September 30, 2013 were included. EPRP includes a manual review of surgical cases to measure type of prophylaxis, and, in the case of vancomycin, clinician-documented reasons for vancomycin use (β-lactam allergy, patient at high risk of methicillin-resistant Staphylococcus aureus (MRSA), facility high rate of MRSA). Descriptive statistics were used to evaluate findings.ResultsAmong 79, 058 surgical procedures at 109 different medical centers, 20,349 (25.7%) received vancomycin either alone or in combination with another agent for prophylaxis. Rates of vancomycin use were the highest for cardiac surgeries (10,455/21,396, 48.9%), followed by orthopedic total joint replacement surgeries (8,044/38,675, 20.8%), vascular surgeries (1,504/8,177, 18.4%) and colorectal surgeries (346/10,810, 3.2%). The most common reason for vancomycin use was a perceived high facility rate of MRSA (7,367, 36.2%) followed by β-lactam allergy (4,855, 23.9%) and high-risk patient (1,420/20,349, 7.0%). There was no reason documented in 5,194 (25.5%). The most common reason for vancomycin use differed by surgical type. Among cardiac and orthopedic cases, high facility rate was the most commonly reported reason, but β-lactam allergy was the most common driver among vascular and colorectal procedures.ConclusionFacility factors are a major driver of peri-operative vancomycin use, more so than β-lactam allergy or patient-level factors, particularly in cardiac and orthopedic surgery. These data suggest that facility-level interventions, such as implementation of specific guidelines, may be helpful for limiting vancomycin use in this population.Disclosures All authors: No reported disclosures.

Opioid use prior to elective surgery is strongly associated with persistent use following surgery: an analysis of 14 354 Medicare patients.

BackgroundPersistent opioid use following total joint replacement (TJR) surgery is common; however, the association between pre‐surgical opioid use and surgery type has not been established. The objective of this study was to determine the association between pre‐surgery opioid use and persistent post‐surgery opioid use in TJR patients compared to other elective surgical patients.MethodsThis is a retrospective cohort study, of univariate and multinomial logistic regression of linked, de‐identified Medicare Benefits Schedule and Pharmaceutical Benefits Schedule data, adjusted for perioperative opioid use, age and sex. Oral morphine equivalents daily doses (OMEDD) were calculated and opioid use was categorized into three mutually exclusive categories for each observation window: low (0–5 OMEDD), moderate (5–10 OMEDD), high (10+ OMEDD). Persistent opioid use was defined as opioid use between 180 and 270 days after the date of surgery.ResultsPersistent opioid use was associated with older age, female gender and pre‐surgery opioid use. There was no increased risk for persistent opioid use for TJR patients compared to other surgical patients. The intensity of pre‐surgery opioid usage is strongly associated with persistent opioid use in all observed surgical patients.ConclusionsOur results suggest that many patients who use opioids prior to surgery will persist in their opioid use following surgery. No association was found between persistent opioid use and TJR surgery, but rather a risk reduction compared to other elective surgeries when associations with opioid use are controlled for. Primary care clinicians and surgeons should monitor the duration and dosage of perioperative opioid use.

Biaxial fatigue crack propagation behavior of ultrahigh molecular weight polyethylene reinforced by carbon nanofibers and hydroxyapatite.

Ultrahigh molecular weight polyethylene (UHMWPE) artificial joint has remained the preferred polymer component in total joint replacement surgery. However, more and more concerns have been raised about the failure of UHMWPE components due to the initiation and propagation of cracks at the notches with fixed functions. For this reason, biaxial fatigue crack growth (FCG) experiments of UHMWPE reinforced by carbon nanofibers (CNF) and hydroxyapatite (HA) were carried out using elastic-plastic fracture mechanics theory. The FCG resistance of UHMWPE, UHMWPE/CNF, and UHMWPE/HA was compared, and the effects of stress ratio (R) value and phase difference on FCG rate were investigated. At the same time, the influence of loading path was considered, and the corresponding crack path was analyzed. Results suggest that UHMWPE/CNF has better FCG resistance and the FCG rate increases with the increase of R value and the existence of 180° phase difference. In addition, crack bifurcation behavior is not observed under nonproportional loading conditions. The findings in this study will provide experimental validation and data support for better clinical application of UHMWPE-modified materials.

Developing and Implementing a Digital Navigation Program to Improve Outcomes for Medicare Bundle Patients Undergoing Joint Replacement Surgery

Background Evidence-based patient education and consistent, timely communication is key to ensuring good outcomes among joint replacement patients. Mount Sinai Hospital (MSH) participates in the mandatory CMS bundle for comprehensive joint replacement (CJR). MSH’s bundled payment strategy focuses on the development of a standardized model of care, built around evidence-based best practices to achieve the triple aims of strengthening population health while controlling cost and improving the quality of care. MSH launched a comprehensive digital navigation program (DNP) to guide joint replacement patients and their caregivers through pre-surgical preparation and recovery. Objective The objective was to improve the quality of care for joint replacement patients through creation of a digital navigation program specifically tailored to Medicare patients (age 65+) across the continuum of care. Methods Mount Sinai App Lab, in collaboration with the Department of Orthopedics, developed three digital therapeutic modules that were delivered through the RxUniverse Digital Medicine platform (Rx.Health, NY). These automated messages, programmed to send at specific times, included exercise instructions, medication reminders, and suggestions for how to prepare the home for optimal recovery. Messages specifically targeted key patient outcomes: length of stay, readmissions, ambulation on postoperative day 0, and discharge disposition. Staff “prescribed” each module to patients to ensure that engagement aligned with their process of care. Results Clinicians, patients, and their caregivers were receptive to the DNP. Patients showed a high rate of engagement, clicking links to educational content 873 times, and patients called their case manager or surgeon’s office to clarify their next steps when prompted. After 9 months, clinical outcomes for the digital navigation program were compared to other Medicare patients who had not received it. DNP patients had significantly shorter length of stay than their peers (2.81 vs 4.31 days). They also had a lower readmission rate (1.9% vs 2.9%) as well as a higher rate of discharge to home (87.8% vs 64.3%) and were more likely to ambulate on the day of surgery (47.9% vs 33.3%). Twenty patients responded to an end-of-program survey about their experience; 18 patients (90%) agreed that the program was helpful with the process of their total joint replacement surgery, 2 patients neither agreed nor disagreed (10%), and 0 patients disagreed. When asked about their satisfaction with the message volume, 19 patients answered “yes, this was the perfect number,” (95%) and 1 patient answered “no, I want fewer messages” (5%). Patient qualitative feedback was very positive. Patients reported, “Texts reassured me and helped me along with my progress and recovery,” and “Good support. Thank you.” A third said, “The texting program serves as a great reminder as what to do and when.” Conclusions The CJR DNP provided a direct, automated channel to educate and support patients at each stage of care. It demonstrated that digital navigation technology can be used even among non-digital native populations. It resulted in a significantly reduced length of stay and hospital readmissions among participating patients. Next steps include scaling the program across the health system and adding Spanish-language support. Similar programs are now being implemented for other surgical and disease use cases.

An Implantable Wireless Inductive Sensor System Designed to Monitor Prosthesis Motion in Total Joint Replacement Surgery.

Currently, the most common method for detecting prosthetic implant loosening is imaging. Unfortunately, imaging methods are imprecise in detecting the early signs of implant loosening. This paper describes a new wireless inductive proximity sensor system for detecting early implant loosening. The loosening of the implant is accurately detected by analyzing the electromagnetic field generated by the passive sensors located around the implant. The sensor system was modeled and simulated using COMSOL, and then tested experimentally. The inductive proximity sensor and the metallic implant form a coupled circuit is tuned to oscillate at a designed frequency. The circuit's integrated controller measures and records specific sensor's parameters such as resistance and inductance of the sensor that are directly related to the distance between the sensor system and the implant. A prototype has been developed and the results show that the designed proximity sensor is capable of measuring the loosening of the hip implant at [Formula: see text]m resolution at distances of less than [Formula: see text], and of [Formula: see text]m resolution at a distance of [Formula: see text]. Furthermore, there is a good correlation between the simulated and experimental results.

Total joint replacement surgery for knee osteoarthritis and other non-traumatic diseases: a network meta-analysis

Total joint replacement surgery for knee osteoarthritis and other non-traumatic diseases: a network meta-analysis

In- vitro evaluation of the bioactivity and the biocompatibility of a novel coated UHMWPE biomaterial for biomedical applications

Ultra-High Molecular Weight Polyethylene (UHMWPE) is the gold standard biomaterial used as a bearing surface in total joint replacement surgeries. However, osteolysis and subsequent implant failure as a result of the production of wear debris may occur at the contacting surfaces. One potential solution to overcome this problem is to strengthen the surface of UHMWPE which can be achieved by adding a thin coating layer made of Polyamide.In this article, a combination of biological and biochemical tests, including cell viability, antibacterial activity (using Escherichia coli and Staphylococcus aureus), and wound healing assays were performed to assess the bioactivity and the biocompatibility of the coated specimens. Additional tests, such as simulated body fluid absorption, Alizarin Red Staining, Scanning Electron Microscopy, Energy-dispersive X-ray spectroscopy, and Fourier-transform infrared spectroscopy techniques were conducted to evaluate the moisture uptake, osteogenic activity, and the morphology of the coated samples. The antibacterial activity test results after 24 h incubation showed that the nylon-coated UHMWPE has significantly higher antibacterial activity compared to the uncoated UHMWPE. The results of wound closure showed that nylon-coated UHMWPE promotes more wound healing compared to the uncoated material that exhibits a similar percentage of wound closure as the control. This is the first study to demonstrate the superiority of the proposed coated biomaterial for wound healing applications with improved antibacterial capabilities.

Patient Outcomes Following Total Joint Replacement Surgery: A Comparison of Hospitals and Ambulatory Surgery Centers

BackgroundFor several years, many orthopedic surgeons have been performing total joint replacements in hospital outpatient departments (HOPDs) and more recently in ambulatory surgery centers (ASCs). In a recent shift, the Centers for Medicare and Medicaid Services began reimbursing for total knee replacement surgery in HOPDs. Some observers have expressed concerns over patient safety for the Medicare population particularly if Centers for Medicare and Medicaid Services extends the policy to include total hip replacement surgery and coverage in ASCs. MethodsThis study used a large claims database of non-Medicare patients to examine inpatient and outpatient total knee replacement and total hip replacement surgery performed on a near-elderly population during 2014-2016. We applied propensity score methods to match inpatients with ASC patients and HOPD patients with ASC patients adjusting for risk using the HHS Hierarchical Condition Categories risk adjustment model. We conducted statistical tests comparing clinical outcomes across the 3 settings and examined relative costs. ResultsReadmissions, postsurgical complications, and payments were lower for outpatients than for inpatients. Within outpatient settings, readmissions and postsurgical complications were lower in ASCs than in HOPDs but payments for ASC patients were higher than payments for HOPD patients. ConclusionOur findings support the argument that outpatient total joint replacement is appropriate for select patients treated in both HOPDs and ASCs, although in the commercially insured population, the latter services may come at a cost. Until further study of outpatient total joint replacement in the Medicare population becomes available, how this will extrapolate to the Medicare population is unknown.

P3. Perioperative immunonutrition in spine and total joint surgery

BACKGROUND CONTEXT In the current era of adding value to health care, modifiable risk factors have become a major focus. Quality and outcomes are now measured, reported, and tied to reimbursement. Recent studies in orthopedic surgery and spine surgery have shown nutritional status to be one of the most significant risk factors for post-operative complications. Our purpose for this study is to evaluate if perioperative nutritional support can reduce post-operative complications and improve outcomes in orthopedic and spine surgery patients. PURPOSE To evaluate if perioperative nutritional support with immunonutrition containing arginine, glutamine, omega 3 fatty acids, and nucleotides can reduce post-operative complications and improve outcomes in orthopedic and spine surgical patients. STUDY DESIGN/SETTING For a 12-month period from November 2016 to October 2017 we prospectively collected data for inpatient total joint replacements and spine surgeries occurring at two hospitals. Surgeries were performed by one of two fellowship trained Orthopedic spine surgeons. PATIENT SAMPLE A total of 125 patients were included. Patients were excluded from the study if they were receiving radiation, or chemotherapy, at the time of surgery or were non compliant with the nutritional protocol. Included patients were adults over the age of 18 undergoing elective spine or total joint replacement surgery OUTCOME MEASURES Postoperative complications, readmissions, reoperations were recorded. Number needed to treat and absolute risk reduction were calculated to evaluate results. METHODS Data were prospectively collected for inpatient total joint replacements and spine surgeries for 12 months beginning November 2016 and ending October 2017. All patients were followed a minimum of 90 days after surgery. The immunonutrition group was instructed to consume two 8 oz bottles of Ricochet Nutrition (Revive Medical, Brighton, MO USA) each day for 6 days before, and 6 days after, surgery. Outcome data was collected on reoperations, readmissions, and complications including: surgical site infections, Pneumonia, UTI, sepsis, and acute MI. RESULTS A total of 125 patients (62 in immunonutrition group and 63 in the control group) were included and no difference was found between the two groups regarding surgery type, comorbidities, sample size, and demographics. The control group had a total of 8 patients with complications after surgery: 1 pneumonia, 3 UTIs, 1 incisional hernia, and 2 deep surgical site infections. There was a total of 3 reoperations and 4 readmissions in the control group. The immunon trition group had no reoperations, no readmissions, and no complications. CONCLUSIONS Our study provides strong evidence that perioperative immunonutrition (containing Arginine, Glutamine, Omega 3 FAs and Nucleotides) reduces complications, reoperations and readmission for inpatient orthopedic and spine surgery patients.; Patient optimization prior to surgery should include optimizing nutritional status with immunonutrition. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

The role of total joint replacement surgery in the orthognathic patient

Alloplastic reconstruction of the temporomandibular joint, commonly referred to as total joint replacement, is used to treat end stage joint disease in a cohort of patients who present with a range of condylar pathology. In considering its role in the management of the orthognathic patient, it is helpful to categorize patients into those with primary pathology of the mandibular condyle or those with primary dentofacial deformity. The success of total joint replacement is predicated by the predictably stable results that are achieved when used in carefully selected clinical scenarios. In this article, we will discuss the role of total joint replacement surgery in the orthognathic patient and highlight its clinical impact by inclusion of a case study.

The effect of femoral head size on volumetric wear rate following total hip joint replacement surgery

Background: Numerous data records that the number of total hip joint replacement is increasing in many parts of the world which also indicates an increase demand for total hip joint replacement and revision surgery. The purpose of this paper is to review the literature regarding the size of femoral head and its relation to the volumetric wear rate of the polyethylene lining of the hip’s acetabular component.Methods: A systematic literature search performed to identify relevant publications for this review in five databases: University of Melbourne Science, Medline/ Pubmed, Cochrane Library, and Ebsco. The search was completed on 6 October 2012 and again on 24 October 2012. The following keywords and phrases were used: total hip joint replacement, femoral head size, wear, polyethylene and arthroplasty.Results: The six studies are all prospective cohort studies with a follow-up time ranging between three to ten years at the minimum. One study conducted by Hammerberg et al. did not mention the minimum length of their follow up however they include a mean follow up period which is 3.6 years. Two studies did not mention the number of patients they are following up. Every other studies mention how many participants included in their study, but these two studies mention how many hips undergo the total hip joint replacement surgery. The number of patients mentioned in the studies vary from the minimum of 42 patients up until 200 patients. The number of hips in each study ranged from 45 hips to 385 hips.Conclusion: This review concludes that the use of larger femoral head size hastens the wear rate of the polyethylene lining of the acetabulum component.

Surface nano-modification by ion beam-assisted deposition alters the expression of osteogenic genes in osteoblasts.

Biomaterials with enhanced biocompatibility are favored in implant studies to improve the outcomes of total joint replacement surgeries. This study tested the hypothesis that nano-structured surfaces for orthopedic applications, produced by the ion beam-assisted deposition method, would enhance osteointegration by altering the expression of bone-associated genes in osteoblasts. The ion beam-assisted deposition technique was employed to deposit nano-films on glass or titanium substrates. The effects of the ion beam-assisted deposition produced surfaces on the human osteosarcoma cell line SAOS-2 at the molecular level were investigated by assays of adhesion, proliferation, differentiation, and apoptosis on coated surfaces versus uncoated cobalt-chrome, as the control. Ion beam-assisted deposition nano-coatings enhanced bone-associated gene expression at initial cell adhesion, proliferation, and differentiation compared to cobalt-chrome surfaces as assessed by polymerase chain reaction techniques. Increased cell proliferation was observed using a nuclear cell proliferation-associated antigen. Moreover, enhanced cell differentiation was determined by alkaline phosphatase activity, an indicator of bone formation. In addition, programmed cell death assessed by annexin V staining and flow cytometry was lower on nano-surfaces compared to cobalt-chrome surfaces. Overall, the results indicate that nano-coated surfaces produced by the ion beam-assisted deposition technique for use on implants were superior to orthopedic grade cobalt-chrome in supporting bone cell adhesion, proliferation, and differentiation and reducing apoptosis. Thus, surface properties altered by the ion beam-assisted deposition technique should enhance bone formation and increase the biocompatibility of bone cell-associated surfaces.

The Reliability and Validity of the Chinese Version of Confusion Assessment Method Based Scoring System for Delirium Severity (CAM-S).

Previous studies showed that the Confusion Assessment Method based delirium severity evaluation tool (CAM-S) had good reliability and validity. However, there is no Chinese version of the CAM-S. Therefore, we set out to perform a prospective investigation in older Chinese patients who had total joint replacement surgery under general anesthesia in Tenth People's Hospital in Shanghai, P.R. China. A total of 576 participants, aged 60 years or older, were screened, 179 participants were enrolled, and 125 of them were included for the final analysis. Pre-operative evaluations were conducted one day before the surgery. Postoperative evaluations were conducted twice daily from postoperative day 1 to day 3. The incidence of postoperative delirium was 24.8%. The Chinese version of CAM-S [including a Short Form (CAM-S Short Form) and a Long Form (CAM-S Long Form)] had an optimal reliability reflected by internal consistency (Cronbach's α= 0.748 and 0.839 for CAM-S Short Form and CAM-S Long Form respectively), split-halves reliability (Pearson correlation coefficient = 0.372 and 0.384 for CAM-S Short Form and CAM-S Long Form respectively), and inter-rater reliability (intra-class correlation coefficients = 0.629 and 0.945 for CAM-S Short Form and CAM-S Long Form respectively). Additionally, the Chinese version of CAM-S also showed a good discriminate validity. The domain scores of CAM-S were inversely correlated with corresponding domain scores of the MMSE. Finally, a receiver operating characteristic (ROC) analysis obtained an optimal cutoff point of 2.5 for CAM-S Short Form and 3.5 for CAM-S Long Form in recognizing delirium diagnosed by CAM. The areas under the ROC were 0.989 (95% CI 0.972 - 1.000, p < 0.001) and 0.964 (95% CI 0.946 - 0.982, p < 0.001), respectively. These data suggest that the Chinese version of CAM-S has good reliability and validity in evaluating postoperative delirium in geriatric Chinese patients and may be a useful tool to assess the severity of delirium.

Peripheral Nerve Blocks and Immediate Postoperative Recovery: A Single-Institution Survey of Perianesthesia Nurses' Preferences and Opinions

To ascertain the preferences of perianesthesia nurses regarding peripheral nerve blocks (PNBs) and their impact on patient recovery after total joint replacement (TJR). Survey of perianesthesia nurses at a single medical center. Fifty-nine perianesthesia nurses completed a 23-question survey on PNBs for TJR. Most agreed PNBs improved patients' pain after knee, hip, and shoulder TJR (35 [92.1%], 35 [92.1%], and 34 [91.9%], respectively). Most felt lower extremity PNBs increased risk of falling (26 [70.3%]), whereas 7 of 35 (20.0%) felt patients fell more after spinal anesthesia than after general anesthesia. Respondents preferred a block to opioid-based analgesia if they were to have lower extremity TJR or total shoulder replacement (100% [30/30 and 33/33]). The perianesthesia nurses surveyed felt PNBs improved pain control and patient recovery despite a perceived risk of falling for lower extremity TJR, and they preferred PNB when considering TJR surgery for themselves.

Clinical pathway efficiency for elective joint replacement surgeries: a case study

PurposeThe purpose of this paper is to define a clinical pathway for total joint replacement (TJR) surgery, estimate the effect of delays between steps of the pathway on wait time for surgery and to identify factors contributing to more efficient operations and challenges to their implementation.Design/methodology/approachThis is a case study with a mixed methods approach. The authors conducted interviews with hospital staff. Data collected in the interviews and through on-site observation were analyzed to map the TJR process and identify the steps of the care pathway. The authors extracted and analyzed data (time stamps) from 60 hospital patient records for each step in the pathway and ran a regression on the duration of the whole trajectory.FindingsThere were wide variations in the delays observed between the seven steps identified. The delay between Step 1 and Step 2 was the only significant variable in predicting the total wait time to surgery. In one hospital, one delay explained 50 percent of the variation. There was misalignment between findings from the qualitative data in terms of strategies implemented to increase efficiency of the clinical pathway to the quantitative data on delays between the steps.Research limitations/implicationsThe study identified the clinical pathway from the consultation with an orthopaedic surgeon to the surgery. However, it did not go beyond the surgery. Future research could investigate the relationship between specific processes and delays between steps of the process and patient outcomes, including length of stay, mobilization and functionality in activities of daily living, as well as potential complications from surgery, readmission and the services required after the patient was discharged.Practical implicationsWait times can be addressed by implementing strategies at the health system level or at the organizational level. The authors found and discuss areas where there could be efficiency gains for health care organizations.Social implicationsStakeholders in care processes are diverse and they each have their preferences in how they practice (in the case of providers) and how they perceive and wish to respond adequately to patients’ needs in contexts that have different norms and approaches. The approach in this study enables a better understanding of the processes, the organizational culture and how these may affect each other.Originality/valueOur mixed methods enabled a process mapping and the identification of factors that significantly affected the efficiency of the TJR surgery process. It combines methods from process engineering with health services and management research. To some extent, this study demonstrates that although managers can define and enforce processes, organizational culture and practices are harder to influence.

Distinct fatty acid signatures in infrapatellar fat pad and synovial fluid of patients with osteoarthritis versus rheumatoid arthritis

BackgroundInfrapatellar fat pad (IFP) has recently emerged as a potential source of inflammation in knee arthropathies. It has been proposed to be one source of adipocytokines, fatty acids (FA), and FA-derived lipid mediators that could contribute to the pathophysiological processes in the knee joint. Alterations in synovial fluid (SF) lipid composition have been linked to both osteoarthritis (OA) and rheumatoid arthritis (RA). The aim of the present study was to compare the FA signatures in the IFP and SF of RA and OA patients.MethodsPairs of IFP and SF samples were collected from the same knees of RA (n = 10) and OA patients (n = 10) undergoing total joint replacement surgery. Control SF samples (n = 6) were harvested during diagnostic or therapeutic arthroscopic knee surgery unrelated to RA or OA. The FA composition in the total lipids of IFP and SF was determined by gas chromatography with flame ionization and mass spectrometric detection.ResultsArthropathies resulted in a significant reduction in the SF proportions of n-6 polyunsaturated FA (PUFA), more pronouncedly in OA than in RA. OA was also characterized with reduced percentages of 22:6n-3 and lower product/precursor ratios of n-3 PUFA. The proportions of total monounsaturated FA increased in both RA and OA SF. Regarding IFP, RA patients had lower proportions of 20:4n-6, total n-6 PUFA, and 22:6n-3, as well as lower product/precursor ratios of n-3 PUFA compared to OA patients. The average chain length of SF FA decreased in both diagnoses and the double bond index in OA.ConclusionsThe observed complex alterations in the FA signatures could have both contributed to but also limited the inflammatory processes and cartilage destruction in the RA and OA knees.

Vx-11e protects against titanium-particle-induced osteolysis and osteoclastogenesis by supressing ERK activity

Wear particle-induced osteolysis around the prosthesis is the most common long-term complication after total joint replacement surgery which often leads to aseptic loosening of the prosthesis. Osteoclasts play key roles in the osteolytic process. Currently there is a lack of clinically effective measures to prevent or treat peri-prosthetic osteolysis and thus identification of new agents that can inhibit the enhanced osteoclastic bone resorption is warranted. Through this study, we discovered that the specific and potent ERK1/2 inhibitor, Vx-11e, can protect against calvarial osteolysis caused by titanium (Ti) particles in vivo. Low doses of Vx-11e mildly reduced osteoclast resorption whilst no calvarial osteolysis was observed with high dose Vx-11e treatment. Histological examination showed fewer osteoclasts and reduced bone erosion in the Vx-11e treated groups. In vitro cellular analyses showed that Vx-11e inhibited osteoclast formation from BMM precursors in response to RANKL, as well as bone resorption by mature osteoclasts. Mechanistically, Vx-11e impaired RANKL-induced ERK1/2 signaling by inhibiting its kinase activity thereby blocking the phosphorylation of downstream substrates. Moreover, Vx-11e significantly reduced the expression of RANKL-mediated genes such as ACP5/TRAcP, CTR, MMP-9, CTSK. Collectively, our data provides evidence for the potential therapeutic use of Vx-11e for the treatment of osteolysis diseases caused by extremely actived osteoclastogenesis.

“I was considering surgery because I believed that was how it was treated”: a qualitative study on willingness for joint surgery after completion of a digital management program for osteoarthritis

To explore, using a qualitative approach, reasons for patients' continued willingness or their shift in willingness for total joint replacement (TJR) surgery, following participation in Joint Academy, a Swedish, digital, non-surgical treatment program for osteoarthritis (OA). Nineteen patients with hip or knee OA were interviewed after finishing their first 6weeks in the treatment program, using a semi-structured interview guide. The interviews were transcribed verbatim and analyzed using a systematic text condensation method. Analysis of the interview data revealed three main categories of reasons provided for the participants' decisions regarding surgery: 1) Various reasons for participating in Joint Academy with three sub-categories: (a) longstanding pain affects daily life, (b) last chance for improvement and (c) mandatory treatment to be eligible for total joint replacements (TJR); 2) Willingness for TJR following treatment, which included four sub-categories: (a) surgery - the last resort, (b) reduced pain and improved functioning, (c) no perceived improvements after treatment, and (d) trust in healthcare providers; and 3) Expectations of TJR. The shift in willingness towards or away from TJR was mainly due to the perceived success of Joint Academy in improving their functioning. Several patients reconsidered their options and had changed their attitude to TJR after participation in a digital program aimed at reducing OA symptoms and improving functioning. These results highlight the importance of providing patients with adequate information about non-surgical management options to facilitate shared decision-making, and possibly reduce the need for surgery.

14-3-3E, a new alarmin candidate, elicits a catabolic and proinflammatory effect involving innate immunity through TLR signaling in osteoarthritis

Purpose: Osteoarthritis (OA) is now considered as a whole-joint disease characterized by cartilage degradation, synovial inflammation and bone remodeling. Recent studies have shown the implication of the innate immune system and low-grade inflammation in OA progression. Our team identified 14-3-3ε as a novel soluble mediator critical in the communication between subchondral bone and cartilage in OA. This protein acts as a potent MMP-3 and MMP-13-stimulatory factor in chondrocytes leading to catabolic phenotype. 14-3-3ε seems to share common characteristics with alarmins, endogenous molecules with intracellular functions that are released in the extracellular media after infection or tissue damage. Alarmins (such as S100 and HMGB1 involved in cartilage degradation) bind to receptors expressed on the surface of cells engaged in host defense and tissue repair. These receptors include the Toll-like receptors, TLR2 and TLR4. Moreover, innate alarmins can stimulate the activation of resident immune cells of the synovium, particularly macrophages leading to synovitis. As well as alarmins, 14-3-3ε could determine macrophage polarization. Our aim is to investigate the interactions between 14-3-3ε and its potential receptors, TLR2 and TLR4. Methods: Primary cultures of chondrocytes were performed from murine cartilage of the C57BL/6J mice (5 days old), and from human cartilage samples, obtained from OA patients undergoing total joint replacement surgery. The receptors TLR2 and TLR4 were blocked by monoclonal antibodies and pharmacologic inhibitors in chondrocytes (15mn) and then stimulated by recombinant 14-3-3ε during 24h. The stimulation by 14-3-3ε was also done on primary cultures of chondrocytes from TLR4 KO or TLR2 KO mice pups. Stimulation by 14-3-3ε has been performed with addition of Polymyxin B to avoid endotoxin effects. Immunocytochemistry was realized on murine chondrocytes with receptors antibodies. Chondrocyte gene expression and release of MMP-3, MMP-13 and IL-6 were evaluated by RT-PCR and ELISA. The direct interaction of 14-3-3ε with TLR2 was measured using Surface plasmonic resonance (SPR) on a Biacore 3000 instrument. Their molecular interaction was modeled in silico using GrammX and Rosetta programs to model the interaction and optimize the predicted conformations, respectively. The best complexes of 14-3-3ε with TLR2 were visually analyzed using PyMOL. M1 polarization of macrophages was performed by activating THP1 cells (ATCC) with PMA during 24h and and followed by 24h stimulation with LPS or 14-3-3ε. Different markers of the M1 type were analysed by ELISA and RT-qPCR to identify the polarisation of macrophages (M1 : TNF, IL-6, IL-1β, MCP1, Nos2). Results: TLR2 and TLR4 receptors were found on murine articular chondrocytes by immunocytochemistry using monoclonal antibodies. Invalidation of TLR2 and TLR4 receptors by blocking antibody in articular chondrocytes reduced significantly mRNA expression and protein release of MMP-3, MMP-13 and IL-6 induced by 14-3-3ε. For MMP3 mRNA expression, the inhibition rate reached 78% with blocking antibodies and 98% with OxPAPC, a TLR2/TLR4 inhibitor. The inhibition rate reached 65% (blocking antibodies), 98% (OxPAPC) for MMP13 and 74% (blocking antibodies) and 93% (OxPAPC) for IL-6. ELISA experiments showed an inhibition rate of 84% (blocking antibodies) and 97% (OxPAPC) for MMP3. Similar rates were observed for IL-6 secretion (83% and 97%). Moreover, the effect of 14-3-3ε on MMP3, MMP13 and IL6 expression was reduced in TLR4-KO and abolished in TLR2-KO chondrocytes. In the Biacore analysis, human recombinant TLR2 and TLR4 were covalently immobilized on CM5 chip. Results demonstrated a direct interaction between recombinant TLR2 and 14-3-3ε (83 RU) and between TLR4 and 14-3-3ε (41 RU). Computational structural analysis identified in silico a putative region of interaction, centered on a phosphorylation site in TLR2. This region of binding is consistent as 14-3-3ε is known to accommodate specifically phosphorylated residues. The affinity measurements between 14-3-3ε and peptides of TLR2 designed accordingly to this phospho-site are currently in progress. Finally, polarization of macrophages stimulated by recombinant 14-3-3ε seems to polarize them toward a M1 inflammatory phenotype. Conclusions: We have discovered 14-3-3ε as a new catabolic factor, produced by the subchondral bone and able to induce a catabolic phenotype on chondrocytes. These effects are mediated, at least in part, by TLR2 or TLR4 signalling, leading to the activation of innate immunity. Taken together, our results designate 14-3-3ε as a novel alarmin in OA, triggering catabolic and inflammatory effects through TLRs signaling. This new alarmin candidate could represent a new target either for therapeutic and/or prognostic purposes.