Aims. This study aimed to investigate the clinical characteristics and outcomes associated with culture-negative limb osteomyelitis patients. Methods. A total of 1,047 limb osteomyelitis patients aged 18 years or older who underwent debridement and intraoperative culture at our clinic centre from 1 January 2011 to 31 December 2020 were included. Patient characteristics, infection eradication, and complications were analyzed between culture-negative and culture-positive cohorts. Results. Of these patients, 264 (25.2%) had negative cultures. Patients with a culture-negative compared with a culture-positive status were more likely to have the following characteristics: younger age (≤ 40 years) (113/264 (42.8%) vs 257/783 (32.8%); p = 0.004), a haematogenous aetiology (75/264 (28.4%) vs 150/783 (19.2%); p = 0.002), Cierny-Mader host A (79/264 (29.9%) vs 142/783 (18.1%); p < 0.001), antibiotic use before sampling (34/264 (12.9%) vs 41/783 (5.2%); p＜0.001), fewer taken samples (n＜3) (48/264 (18.2%) vs 60/783 (7.7%); p＜0.001), and less frequent presentation with a sinus (156/264 (59.1%) vs 665/783 (84.9%); p < 0.001). After initial treatments of first-debridement and antimicrobial, infection eradication was inferior in culture-positive osteomyelitis patients, with a 2.24-fold increase (odds ratio 2.24 (95% confidence interval 1.42 to 3.52)) in the redebridement rate following multivariate analysis. No statistically significant differences were found in long-term recurrence and complications within the two-year follow-up. Conclusion. We identified several factors being associated with the culture-negative result in osteomyelitis patients. In addition, the data also indicate that culture negativity is a positive prognostic factor in early infection eradication. These results constitute the basis of optimizing clinical management and patient consultations. Cite this article: Bone Joint J 2024;106-B(7):720–727

Aims. Musculoskeletal infection is a devastating complication in both trauma and elective orthopaedic surgeries that can result in significant morbidity. Aim of this study was to assess the effectiveness and complications of local antibiotic impregnated dissolvable synthetic calcium sulphate beads (Stimulan Rapid Cure) in the hands of different surgeons from multiple centres in surgically managed bone and joint infections. Methods. Between January 2019 and December 2022, 106 patients with bone and joint infections were treated by five surgeons in five hospitals. Surgical debridement and calcium sulphate bead insertion was performed for local elution of antibiotics in high concentration. In all, 100 patients were available for follow-up at regular intervals. Choice of antibiotic was tailor made for each patient in consultation with microbiologist based on the organism grown on culture and the sensitivity. In majority of our cases, we used a combination of vancomycin and culture sensitive heat stable antibiotic after a thorough debridement of the site. Primary wound closure was achieved in 99 patients and a split skin graft closure was done in one patient. Mean follow-up was 20 months (12 to 30). Results. Overall, six out of 106 patients (5.6%) presented with sepsis and poorly controlled comorbid conditions, and died in the hospital within few days of index surgery. Out of the remaining 100 patients, control of infection was achieved in 95 patients (95%). Persistence of infection was noted in five (5%) patients. Out of these 95 patients that had good control of infection, four patients (4.2%) with gap nonunion needed Masquelet procedure to achieve union. Conclusion. Our multicentre experience confirmed that surgical debridement along with calcium sulphate bead insertion was effective in treating bone and joint infections without any side effects and complications. Cite this article: Bone Jt Open 2023;4(7):516–522

As arthroplasty demand grows worldwide, the need for a novel cost-effective treatment option for articular cartilage (AC) defects tailored to individual patients has never been greater. 3D bioprinting can deposit patient cells and other biomaterials in user-defined patterns to build tissue constructs from the “bottom-up,” potentially offering a new treatment for AC defects. Novel composite bioinks were created by mixing different ratios of methacrylated alginate (AlgMA) with methacrylated gelatin (GelMA) and collagen. Chondrocytes and mesenchymal stem cells (MSCs) were then encapsulated in the bioinks and 3D bioprinted using a custom-built extrusion bioprinter. UV and double-ionic (BaCl2 and CaCl2) crosslinking was deployed following bioprinting to strengthen bioink stability in culture. Chondrocyte and MSC spheroids were also bioprinted to accelerate cell growth and development of ECM in bioprinted constructs. Excellent viability of chondrocytes and MSCs was seen following bioprinting (>95%) and maintained in culture, with accelerated cell growth seen with inclusion of cell spheroids in bioinks (p<0.05). Bioprinted 10mm diameter constructs maintained shape in culture over 28 days, whilst construct degradation rates and mechanical properties were improved with addition of AlgMA (p<0.05). Composite bioinks were also injected into in vitro osteochondral defects and crosslinked in situ, with maintained cell viability and repair of osteochondral defects seen over a 14-day period. In conclusion, we developed novel composite bioinks that can be triple-crosslinked, facilitating successful chondrocyte and MSC growth in 3D bioprinted scaffolds and in vitro repair of an osteochondral defect model. This offers hope for a new approach to treating AC defects

Aims. Deep surgical site infection (SSI) remains an unsolved problem after hip fracture. Debridement, antibiotic, and implant retention (DAIR) has become a mainstream treatment in elective periprosthetic joint infection; however, evidence for DAIR after infected hip hemiarthroplaty is limited. Methods. Patients who underwent a hemiarthroplasty between March 2007 and August 2018 were reviewed. Multivariable binary logistic regression was performed to identify and adjust for risk factors for SSI, and to identify factors predicting a successful DAIR at one year. Results. A total of 3,966 patients were identified. The overall rate of SSI was 1.7% (51 patients (1.3%) with deep SSI, and 18 (0.45%) with superficial SSI). In all, 50 patients underwent revision surgery for infection (43 with DAIR, and seven with excision arthroplasty). After adjustment for other variables, only concurrent urinary tract infection (odds ratio (OR) 2.78, 95% confidence interval (CI) 1.57 to 4.92; p < 0.001) and increasing delay to theatre for treatment of the fracture (OR 1.31 per day, 95% CI 1.12 to 1.52; p < 0.001) were predictors of developing a SSI, while a cemented arthroplasty was protective (OR 0.54, 95% CI 0.31 to 0.96; p = 0.031). In all, nine patients (20.9%) were alive at one year with a functioning hemiarthroplasty following DAIR, 20 (46.5%) required multiple surgical debridements after an initial DAIR, and 18 were converted to an excision arthroplasty due to persistent infection, with six were alive at one year. The culture of any gram-negative organism reduced success rates to 12.5% (no cases were successful with methicillin-resistant Staphylococcus aureus or Pseudomonas infection). Favourable organisms included Citrobacter and Proteus (100% cure rate). The all-cause mortality at one year after deep SSI was 55.87% versus 24.9% without deep infection. Conclusion. Deep infection remains a devastating complication regardless of the treatment strategy employed. Success rates of DAIR are poor compared to total hip arthroplasty, and should be reserved for favourable organisms in patients able to tolerate multiple surgical procedures. Cite this article: Bone Jt Open 2021;2(11):958–965

Gram staining is used as an initial indicator of synovial joint infection but has widely varied false negative rates in the literature. Clinical decisions are often made on the basis of gram stain results, such as whether a patient requires urgent surgery, and therefore it is important to understand the tests efficacy. A retrospective review of synovial fluid aspirates in NHS Tayside for the years 2017 and 2018 was performed from the departmental microbiology database. Aspirates of large joints were included (hip, knee, shoulder, wrist, elbow, ankle). Any joints with prosthesis were excluded, including fixation metalwork. Any abscess overlying a joint that was not proven to penetrate the joint was also excluded. Initial gram stain results and formal culture results were reviewed. Final culture results were considered to be the gold standard to compare gram stain results to. 2167 samples were reviewed. Of these 1552 were excluded base on inclusion criteria. Of the remaining 615, 120 (19.5%) were culture positive. There were 33 positive gram stain results, 1 false positive and 32 true positive results. The sensitivity was 26.67% with a specificity of 99.80% (p=0.0001). The negative predictive value is 84.88% (CI 83.44% – 86.21%). These results show that gram stain tests of native joints have a low sensitivity and poor negative predictive value. This is reflected in the current literature with prosthetic joints. Based on this study caution should be used when interpreting a negative gram stain result with appropriate safety netting and follow up required alongside clinical assessment

The role of mesenchymal stem cells (MSCs) in enhancing healing process has been examined with allogeneic and xenogeneic cells in transplantation models. However, certain factors might limit the use of allogeneic cells in clinical practice, (e.g. disease transmission, ethical issues and patient acceptance). Adipose tissue represents an abundant source for autologous cells. The aim of this study was to evaluate adipose-derived autologous cells for preventing non-union. Adults male Wistar rats (n=5) underwent a previously published surgical procedure known to result in non-union if no treatment is given. This consisted of a mid-shaft tibial osteotomy with peri/endosteal stripping stabilised by intramedullary nail fixation with a 1mm gap maintained by a spacer. During the same operation, ipsilateral inguinal subcutaneous fat was harvested and processed for cell isolation. After three weeks in culture, the cell number reached 5×106 and were injected into the fracture site. At the end of the experiment, all tibias (injected with autologous fat-MSCs) developed union. These were compared with a control group injected with PBS (n=4) and with allogenic (n=5) and xenogeneic (n=6) cell transplantation groups. The amount of callus was noticeably large in the autologous cell group and the distal-callus index was significantly greater than that of the other groups, P-value =<0.05, unpaired t-test, corrected by Benjamini & Hochberg. We report a novel method for autologous MSCs implantation to stimulate fracture healing. Local injection of autologous fat-MSCs into the fracture site resulted in a solid union in all the tibias with statistically significantly greater amounts of callus

Nasal carriers of methicillin sensitive Staphylococcus aureus (MSSA) have an increased risk for health-care associated infections. There is currently no national screening policy for the detection of MSSA in the UK. This study aimed to: evaluate the diagnostic performance of molecular and culture techniques in MSSA screening, determine the cause of any discrepancy between the diagnostic techniques, and model the potential effect of different diagnostic techniques on MSSA detection in orthopaedic patients. Paired nasal swabs for PCR assay and culture of S. aureus were collected from a study population of 273 orthopaedic outpatients due to undergo joint replacement surgery. The prevalence of MSSA nasal colonisation was found to be between 22.4–35.6%. The current standard direct culturing methods for detecting S. aureus significantly underestimated the prevalence (p=0.005), failing to identify its presence in ∼1/3 of patients undergoing joint replacement surgery. Modelling these results to national surveillance data, it was estimated that 800–1200 MSSA surgical site infections could be prevented annually in the UK by using alternative diagnostic methods to direct culture in pre-operative MSSA screening and eradication programmes

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The aim of the present study was to assess the outcomes of the induced membrane technique (IMT) for the management of infected segmental bone defects, and to analyze predictive factors associated with unfavourable outcomes.

Antimicrobial resistance (AMR) is projected to result in 10 million deaths every year globally by 2050. Without urgent action, routine orthopaedic operations could become high risk and musculoskeletal infections incurable in a “post-antibiotic era.” However, current methods of studying AMR processes including bacterial biofilm formation are 2D in nature, and therefore unable to recapitulate the 3D processes within in vivo infection. Within this study, 3D printing was applied for the first time alongside a custom-developed bioink to bioprint 3D bacterial biofilm constructs from clinically relevant species including Staphylococcus aureus (MSSA), Methicillin-resistant staphylococcus aureus (MRSA), Escherichia coli and Pseudomonas aeruginosa. Bacterial viability and biofilm formation in bioprinted constructs was excellent, with confocal laser scanning microscopy (CSLM) used to demonstrate biofilm production and maturation over 28 days. Bioprinted 3D MRSA and MSSA biofilm constructs had greater resistance to antimicrobials than corresponding two-dimensional (2D) cultures. Thicker 3D E.coli biofilms had greater resistance to tetracycline than thinner constructs over 7 days of treatment. Raman spectroscopy was also adapted in a novel approach to non-invasively diagnose 3D bioprinted biofilm constructs located within a joint replacement model. In conclusion, mature bacterial biofilm constructs were reproducibly 3D bioprinted for the first time using clinically relevant bacteria. This methodology allows the study of antimicrobial biofilm penetration in 3D, and potentially aids future antimicrobial research, replicating joint infection more closely than current 2D culture models. Furthermore, by deploying Raman spectroscopy in a novel fashion, it was possible to diagnose 3D bioprinted biofilm infections within a joint replacement model

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This study aimed to describe practice variation in the use of total hip arthroplasty (THA) for older patients with femoral neck fracture and to determine the association between patient, surgeon, and institution factors and treatment with THA.

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Fracture-related infections (FRIs) are a devastating complication of fracture management. However, the impact of FRIs on mental health remains understudied. The aim of this study was a longitudinal evaluation of patients’ psychological state, and expectations for recovery comparing patients with recurrent FRI to those with primary FRI.

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The aim of this study was to perform the first population-based description of the epidemiological and health economic burden of fracture-related infection (FRI).

Aims. This study aimed to investigate the role of quantitative histological analysis in the diagnosis of fracture-related infection (FRI). Patients and Methods. The clinical features, microbiology culture results, and histological analysis in 156 surgically treated nonunions were used to stratify the likelihood of associated infection. There were 64 confirmed infected nonunions (one or more confirmatory criteria: pus, sinus, and bacterial growth in two or more samples), 66 aseptic nonunions (no confirmatory criteria), and 26 possibly infected nonunions (pathogen identified from a single specimen and no confirmatory criteria). The histological inflammatory response was assessed by average neutrophil polymorph (NPs) counts per high-power field (HPF) and compared with the established diagnosis. Results. Assuming a cut-off of over five neutrophils per high-power field to diagnose septic nonunion, there was 80% sensitivity and 100% specificity (accuracy 90%). Using a cut-off of no neutrophils seen in any high-power field to diagnose aseptic nonunion, there was a sensitivity of 85% and a specificity of 98% (accuracy 92%). Conclusion. Histology can be used in a bimodal fashion as a diagnostic test for FRI. The presence of more than five NPs/HPF had a positive predictive value for infected nonunion of 100%, while the complete absence of any NPs is almost always indicative of an aseptic nonunion (positive predictive value of 98%). Cite this article: Bone Joint J 2018;100-B:966–72

The burden of osteoporosis (OP), and its accompanied low energy fractures, is ever increasing. Targeted therapies are under development to stem the tide of the disease, with microRNAs identified as biomarkers and potential targets. Assessing the functional capacity of bone marrow mesenchymal stromal cells (BMSC) from patients with low energy neck of femur fractures (NOF) will identify the expected outcomes to be achieved from new, targeted osteogenic therapies. Two patient groups were assessed; low energy NOF and osteoarthritic. Bone marrow aspirates were taken at time of arthroplasty surgery. The adherent fraction was cultured and assessed by flow cytometry, microRNA expression and differentiation functionality. Both patient groups demonstrated characteristic extracellular markers of BMSCs. 3 key markers were significantly reduced in their expression in the NOF group (CD 90, 13, 166 P=0.0286). Reduced differentiation capacity was observed in the NOF group when cultured in osteogenic and adipogenic culture medium. 105 microRNAs were seen to be significantly dysregulated, with microRNAs known to be crucial to osteogenesis and disease process such as osteoporosis abnormally expressed. This data demonstrates the impaired functional capacity of BMSCs and their abnormal microRNA expression in patients who suffer a low energy NOF. Future targeted therapies for OP must address this to maximise their restorative effect on diseased bone. The important role microRNAs can play as biomarkers and target sites has been further reinforced

Aims. Currently, the most common approach for the management of a chronic PJI is a Two-Stage Replacement; because of success rates exceeding 90% when using an antibiotic impregnated cement spacer. Reliable information regarding the etiologic microorganism and its sensitivities is essential to select the antimicrobial therapy that should be used locally in the bone cement spacer during the first stage surgery as well as to select the appropriate microbiological systemic agent. Diagnostic algorithms focus to the importance of joint aspiration cultures although in the modern literature, preoperative joint aspiration has a broad range of values of sensitivity and the proportion of “dry-aspirations” is not well assessed. This low sensitivity of aspiration fluid samples in chronic-PJI is partly attributable to the fact that the majority of the microorganisms in these infections grow in biofilms attached to the implant. We have developed this biopsy technique in an effort to improve the identification rates of the causative organism. Materials and methods. A sample is harvested through a 4 mm bone trephine and the target is the bone-prosthesis gap. We have compared the results of preoperative PIB with the results of cultures from intra-operative tissue collected during the first stage surgery. In both cases a prolonged culture protocol (10 days) in enrichment media was used. On the basis of this relation, sensitivity, specificity, positive and negative predictive values and accuracy were calculated. Results. Twenty-four PIB were done on the 24 patients (10 hips and 14 knees) who subsequently underwent two-stage revision surgery because of high suspicion of PJI between January 2007 and December 2009. A retrospective analysis was performed in these 24 patients (13 women and 11 men) in the mean age of 70 years (from 63 to 88 years old). Nineteen of the cases were primary and 5 were revision arthroplasty. Nineteen patients (79%) were positive for infection from operative tissue cultures. The sensitivity was 0.79 (95% CI, 0.54–0.93); the specificity was 0.80 (95% CI, 0,30–0.99), the positive predictive value was 0.94 (95% CI, 0.67–0.99), the negative predictive value was 0.50 (95% CI, 17.5–82.5) and the accuracy was 0.79. Conclusion. PIB is a useful test to, preoperatively, isolate the infecting bacteria. The values of sensitivity, specificity and accuracy are on the average of the currently published with joint aspiration or biopsy samples cultures. Although comparative study is necessary we believe that the PIB could be useful in cases with high suspicion of PJI and negative joint aspiration cultures and in cases where no fluid is aspired from the joint, in order to preoperatively isolate the infecting bacteria

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Monocyte-lymphocyte ratio (MLR) or neutrophil-lymphocyte ratio (NLR) are useful for diagnosing periprosthetic joint infection (PJI), but their diagnostic values are unclear for screening fixation-related infection (FRI) in patients for whom conversion total hip arthroplasty (THA) is planned after failed internal fixation for femoral neck fracture.

Prosthetic joint infections provide complex management, due to often-difficult diagnosis, need for multiple surgeries and increased technical and financial requirements. “2 in 1” single stage approaches have been advocated due to reduction in risks, costs and complications. This study aimed to investigate the results of single stage revision using metaphyseal sleeves for infected primary Total Knee Replacement (TKR). Prospective data was collected on all patients presenting with an infected primary TKR over an 8-year period (2009–17). All revision procedures were undertaken in a single stage using metaphyseal sleeves. 26 patients were included, 2 of which had previously failed 2 stage revision and 3 failed DAIR procedures. Mean age was 72.5. Mean BMI was 33.4. Median ASA 2. Mean time to revision was 3.5 years range 3 months to 12 years. Six patients had actively discharging sinuses at the time of surgery. Only 4 of the 26 patients had no positive microbiological cultures from deep tissue samples or joint aspirates. Only one patient has a recurrence of infection. This patient did not require further surgery and is treated on long term antibiotic suppression and is systemically well. There were statistically significant improvements in both the pain and function component of AKSS scores. There was no significant improvement in flexion, however mean extension and total range of movement both showed statistically significant improvements. Using Metaphyseal sleeves in single stage revision for infected TKR are safe and lead to an improvement in pain, function and have excellent efficacy for eradication of infection

Tranexamic acid (TXA) is an anti-fibrinolytic medication commonly used to reduce peri-operative bleeding. Increasingly, topical administration as an intra-articular injection or peri-operative wash is being administered at concentrations between 10–100mg/ml. This study investigated effects of TXA on human periarticular tissues and primary cell cultures using clinically relevant concentrations. Tendon, synovium and cartilage obtained from routine orthopaedic surgeries were used ex vivo or cultured for in vitro studies using various concentrations of TXA. They were stained with 5-chloromethylfluorescein diacetate and propidium iodide and imaged using confocal microscopy to identify the proportion of live and dead cells. The in vitro effect of TXA on primary cultured tenocytes, synovial like fibroblast (FLS) cells and chondrocytes was investigated using cell viability assays (MTT), fluorescent microscopy and multi-protein apoptotic arrays for cell death. There was significant (p<0.01) increase in cell death in all tissue treated with 100mg/ml TXA, ex vivo. MTT assays revealed significant (p<0.05) decrease in cell viability following treatment with 50 or 100mg/ml of TXA within 4 hours of all cell types cultured in vitro. Additionally, there was significant (p<0.05) increase in cell apoptosis detected by fluorescent microscopy within 1 hour of exposure to TXA. Furthermore, multi-protein apoptotic arrays detected increased apoptotic proteins within 1 hour of TXA treatment in tenocytes and FLS cells. Our study provides evidence of TXA cytotoxicity to human peri-articular tissues ex vivo and in vitro at concentrations and durations of treatment routinely used in clinical environments. Clinicians should therefore show caution when considering use of topical TXA administration

Nanoscale topography increases the bioactivity of a material and stimulates specific responses (third generation biomaterial properties) at the molecular level upon first generation (bioinert) or second generation (bioresorbable or bioactive) biomaterials. We developed a technique (based upon the effects of nanoscale topography) that facilitated the in vitro expansion of bone graft for subsequent implantation and investigated the optimal conditions for growing new mineralised bone in vitro. Two topographies (nanopits and nanoislands) were embossed into the bioresorbable polymer Polycaprolactone (PCL). Three dimensional cell culture was performed using double-sided embossing of substrates, seeding of both sides, and vertical positioning of substrates. The effect of Hydroxyapatite, and chemical stimulation were also examined. Human bone marrow was harvested from hip arthroplasty patients, the mesenchymal stem cells culture expanded and used for cellular analysis of substrate bioactivity. The cell line specificity and osteogenic behaviour was demonstrated through immunohistochemistry, confirmed by real-time PCR and quantitative PCR. Mineralisation was demonstrated using alizarin red staining. Results showed that the osteoinduction was optimally conferred by the presence of nanotopography, and also by the incorporation of hydroxyapatite (HA) into the PCL. The nanopit topography and HA were both superior to the use of BMP2 in the production of mineralised bone tissue. The protocol from shim production to bone marrow harvesting and vertical cell culture on nanoembossed HaPCL has been shown to be reproducible and potentially applicable to economical larger scale production

Background. There are several case reports of chondrolysis following joint arthroscopy. Continuous post-operative infusion of local anaesthetic solutions, especially 0.5% Bupivacaine, has been implicated as the causative factor in many of these cases. Recent in vitro studies have shown that even a single exposure of articular cartilage to different local anaesthetic solutions can cause apoptosis and mitochondrial dysfunction in chondrocytes leading to cell death. There is currently no study looking at methods to prevent this toxicity of local anaesthetic solutions to articular cartilage. Glucosamine has a protective and reparative effect on articular cartilage and a Cochrane review in 2007 found that it provides mild benefit in pain and function in patients with arthritis. Aims. Oncologic: To compare the effect of a single exposure, in vitro, of different local anaesthetic solutions on human articular cartilage. To investigate the protective and reparative effects of Glucosamine on articular cartilage exposed to 0.5% Bupivacaine. Methods. Chondral explants (n = 354) were obtained from femoral heads of 14 fracture neck of patients undergoing hemiarthroplasty. To compare the effect of local anaesthetics, each specimen was exposed to one of 8 test solutions for one hour. After this exposure, the specimens were washed and incubated in culture medium containing radio-labelled 35-sulphur for 16 hours. The unbound radioactivity was then washed off and the chondral specimens were digested with proteinase for 24 hours. The uptake of 35-S by each specimen was measured and this gave an estimate of proteoglycan metabolism. Test solutions: 1. 1% Lidocaine; 2. 2% Lidocaine; 3. 0.25% Bupivacaine; 4. 0.5% Bupivacaine,. 5. 0.5% Levo-Bupivacaine; 6. Control solution of M199 culture medium. 7. To investigate its protective effect, 100 micrograms of Glucosamine was added along with 0.5% Bupivacaine; 8. To investigate the reparative effect of Glucosamine, the specimen was exposed to 0.5% Bupivacaine for one hour. After washing, 100 mcg of Glucosamine was added to the culture medium in which the chondral specimen was incubated. Results. Compared to the control culture medium, the inhibition of proteoglycan metabolism was 54% with 1% Lidocaine (p<0.001), 75% with 2% Lidocaine (p<0.01), 50% with 0.25% Bupivacaine (p = 0.04), 78% with 0.5% Bupivacaine (p<0.001) and 73% with 0.5% Levo-Bupivacaine (p<0.001). Adding Glucosamine for protection reduced the toxicity of 0.5% Bupivacaine to 43%, compared to 78% without. However, Glucosamine was not able to repair the damage caused by 0.5% Bupivacaine, with inhibition of proteoglycan metabolism at 70% even after 16 hours of incubation. Conclusion. All local anaesthetic solutions tested were toxic to articular cartilage, 0.5% Bupivacaine being the worst offender. Higher concentrations were more harmful. The addition of Glucosamine to 0.5% Bupivacaine protected against its toxicity to articular cartilage but was not able to repair the damage caused