Objective. To study the effect of hyaluronic acid (HA) on local anaesthetic chondrotoxicity in vitro. Methods. Chondrocytes were harvested from bovine femoral condyle cartilage and isolated using collagenase-containing media. At 24 hours after seeding 15 000 cells per well onto a 96-well plate, chondrocytes were treated with media (DMEM/F12 + ITS), PBS, 1:1 lidocaine (2%):PBS, 1:1 bupivacaine (0.5%):PBS, 1:1 lidocaine (2%):HA, 1:1 bupivacaine (0. 5%):HA, or 1:1 HA:PBS for one hour. Following treatment, groups had conditions removed and 24-hour incubation. Cell viability was assessed using PrestoBlue and confirmed visually using fluorescence microscopy. Results. Media-treated groups had a mean of 1.55×10. 4. cells/well (. sem. 783). All treated cells showed statistically significant reduced viability when compared with media alone (all p < 0.003). Cells treated with bupivacaine + HA (6.70×10. 3. cells/well (. sem. 1.10×10. 3. )) survived significantly more than bupivacaine (2.44×10. 3. cells/well (. sem . 830)) (p < 0.001). Lidocaine + HA (1.45×10. 3. cells/well (. sem. 596)) was not significantly more cytotoxic than lidocaine (2.24×10. 3. cells/well (. sem. 341)) (p = 0.999). There was no statistical difference between the chondrotoxicities of PBS (8.49×10. 3. cells/well (. sem. 730) cells/well) and HA (4.75×10. 3. cells/well (. sem. 886)) (p = 0.294). Conclusions. HA co-administration reduced anaesthetic cytotoxicity with bupivacaine but not lidocaine, suggesting different mechanisms of injury between the two. Co-administered intra-articular injections of HA with bupivacaine, but not lidocaine, may protect articular chondrocytes from local anaesthetic-associated death. Cite this article: Bone Joint Res 2013;2:270–5

Objectives. Intra-articular injections of local anaesthetics (LA), glucocorticoids (GC), or hyaluronic acid (HA) are used to treat osteoarthritis (OA). Contrast agents (CA) are needed to prove successful intra-articular injection or aspiration, or to visualize articular structures dynamically during fluoroscopy. Tranexamic acid (TA) is used to control haemostasis and prevent excessive intra-articular bleeding. Despite their common usage, little is known about the cytotoxicity of common drugs injected into joints. Thus, the aim of our study was to investigate the effects of LA, GC, HA, CA, and TA on the viability of primary human chondrocytes and tenocytes in vitro. Methods. Human chondrocytes and tenocytes were cultured in a medium with three different drug dilutions (1:2; 1:10; 1:100). The following drugs were used to investigate cytotoxicity: lidocaine hydrochloride 1%; bupivacaine 0.5%; triamcinolone acetonide; dexamethasone 21-palmitate; TA; iodine contrast media; HA; and distilled water. Normal saline served as a control. After an incubation period of 24 hours, cell numbers and morphology were assessed. Results. Using LA or GC, especially triamcinolone acetonide, a dilution of 1:100 resulted in only a moderate reduction of viability, while a dilution of 1:10 showed significantly fewer cell counts. TA and CA reduced viability significantly at a dilution of 1:2. Higher dilutions did not affect viability. Notably, HA showed no effects of cytotoxicity in all drug dilutions. Conclusion. The toxicity of common intra-articular injectable drugs, assessed by cell viability, is mainly dependent on the dilution of the drug being tested. LA are particularly toxic, whereas HA did not affect cell viability. Cite this article: P. Busse, C. Vater, M. Stiehler, J. Nowotny, P. Kasten, H. Bretschneider, S. B. Goodman, M. Gelinsky, S. Zwingenberger. Cytotoxicity of drugs injected into joints in orthopaedics. Bone Joint Res 2019;8:41–48. DOI: 10.1302/2046-3758.82.BJR-2018-0099.R1

When transferring tissue regenerative strategies involving skeletal stem cells to human application, consideration needs to be given to factors that may affect the function of the cells that are transferred. Local anaesthetics are frequently used during surgical procedures, either administered directly into the operative site or infiltrated subcutaneously around the wound. The aim of this study was to investigate the effects of commonly used local anaesthetics on the morphology, function and survival of human adult skeletal stem cells. Cells from three patients who were undergoing elective hip replacement were harvested and incubated for two hours with 1% lidocaine, 0.5% levobupivacaine or 0.5% bupivacaine hydrochloride solutions. Viability was quantified using WST-1 and DNA assays. Viability and morphology were further characterised using CellTracker Green/Ethidium Homodimer-1 immunocytochemistry and function was assessed by an alkaline phosphatase assay. An additional group was cultured for a further seven days to allow potential recovery of the cells after removal of the local anaesthetic. A statistically significant and dose dependent reduction in cell viability and number was observed in the cell cultures exposed to all three local anaesthetics at concentrations of 25% and 50%, and this was maintained even following culture for a further seven days. This study indicates that certain local anaesthetic agents in widespread clinical use are deleterious to skeletal progenitor cells when studied in vitro; this might have relevance in clinical applications

Peri-tendinous injection of local anaesthetic, both alone and in combination with corticosteroids, is commonly performed in the treatment of tendinopathies. Previous studies have shown that local anaesthetics and corticosteroids are chondrotoxic, but their effect on tenocytes remains unknown. We compared the effects of lidocaine and ropivacaine, alone or combined with dexamethasone, on the viability of cultured bovine tenocytes. Tenocytes were exposed to ten different conditions: 1) normal saline; 2) 1% lidocaine; 3) 2% lidocaine; 4) 0.2% ropivacaine; 5) 0.5% ropivacaine; 6) dexamethasone (dex); 7) 1% lidocaine+dex; 8) 2% lidocaine+dex; 9) 0.2% ropivacaine+dex; and 10) 0.5% ropivacaine+dex, for 30 minutes. After a 24-hour recovery period, the viability of the tenocytes was quantified using the CellTiter-Glo viability assay and fluorescence-activated cell sorting (FACS) for live/dead cell counts. A 30-minute exposure to lidocaine alone was significantly toxic to the tenocytes in a dose-dependent manner, but a 30-minute exposure to ropivacaine or dexamethasone alone was not significantly toxic. Dexamethasone potentiated ropivacaine tenocyte toxicity at higher doses of ropivacaine, but did not potentiate lidocaine tenocyte toxicity. As seen in other cell types, lidocaine has a dose-dependent toxicity to tenocytes but ropivacaine is not significantly toxic. Although dexamethasone alone is not toxic, its combination with 0.5% ropivacaine significantly increased its toxicity to tenocytes. These findings might be relevant to clinical practice and warrant further investigation

The Cochrane Collaboration has produced five new reviews relevant to bone and joint surgery since the publication of the last Cochrane Corner These reviews are relevant to a wide range of musculoskeletal specialists, and include reviews in Morton’s neuroma, scoliosis, vertebral fractures, carpal tunnel syndrome, and lower limb arthroplasty.

Objectives

We studied subchondral intraosseous pressure (IOP) in an animal model during loading, and with vascular occlusion. We explored bone compartmentalization by saline injection.

Objectives

We have increased the dose of tranexamic acid (TXA) in our enhanced total joint recovery protocol at our institution from 15 mg/kg to 30 mg/kg (maximum 2.5 g) as a single, intravenous (IV) dose. We report the clinical effect of this dosage change.

Objectives

Osteoarthritis (OA) is the most common form of arthritis, affecting approximately 15% of the human population. Recently, increased concentration of nitric oxide in serum and synovial fluid in patients with OA has been observed. However, the exact role of nitric oxide in the initiation of OA has not been elucidated. The aim of the present study was to investigate the role of nitric oxide in innate immune regulation during OA initiation in rats.

Objectives

Rotator cuff tears are among the most frequent upper extremity injuries. Current treatment strategies do not address the poor quality of the muscle and tendon following chronic rotator cuff tears. Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor that activates many genes that are important in skeletal muscle regeneration. HIF-1α is inhibited under normal physiological conditions by the HIF prolyl 4-hydroxylases (PHDs). In this study, we used a pharmacological PHD inhibitor, GSK1120360A, to enhance the activity of HIF-1α following the repair of a chronic cuff tear, and measured muscle fibre contractility, fibrosis, gene expression, and enthesis mechanics.

Objectives

Despite the fact that research fraud and misconduct are under scrutiny in the field of orthopaedic research, little systematic work has been done to uncover and characterise the underlying reasons for academic retractions in this field. The purpose of this study was to determine the rate of retractions and identify the reasons for retracted publications in the orthopaedic literature.

Objectives

To explore the therapeutic potential of combining bone marrow-derived mesenchymal stem cells (BM-MSCs) and hydroxyapatite (HA) granules to treat nonunion of the long bone.

Ketamine has been used in combination with a variety of other agents for intra-articular analgesia, with promising results. However, although it has been shown to be toxic to various types of cell, there is no available information on the effects of ketamine on chondrocytes.

We conducted a prospective randomised controlled study to evaluate the effects of ketamine on cultured chondrocytes isolated from rat articular cartilage. The cultured cells were treated with 0.125 mM, 0.250 mM, 0.5 mM, 1 mM and 2 mM of ketamine respectively for 6 h, 24 hours and 48 hours, and compared with controls. Changes of apoptosis were evaluated using fluorescence microscopy with a 490 nm excitation wavelength. Apoptosis and eventual necrosis were seen at each concentration. The percentage viability of the cells was inversely proportional to both the duration and dose of treatment (p = 0.002 and p = 0.009). Doses of 0.5 mM, 1 mM and 2mM were absolutely toxic.

We concluded that in the absence of solid data to support the efficacy of intra-articular ketamine for the control of pain, and the toxic effects of ketamine on cultured chondrocytes shown by this study, intra-articular ketamine, either alone or in combination with other agents, should not be used to control pain.

Cite this article: Bone Joint J 2014; 96-B:989–94.

Objectives

There are various pin-in-plaster methods for treating fractures of the distal radius. The purpose of this study is to introduce a modified technique of ‘pin in plaster’.

Objectives

To review the current best surgical practice and detail a multi-disciplinary approach that could further reduce joint replacement infection.

We welcome letters to the Editor concerning articles that have recently been published. Such letters will be subject to the usual stages of selection and editing; where appropriate the authors of the original article will be offered the opportunity to reply.

Objectives

The aim of this experimental study on New Zealand’s white rabbits was to investigate the transplantation of autogenous growth plate cells in order to treat the injured growth plate. They were assessed in terms of measurements of radiological tibial varus and histological characteristics.

Objectives

Electromagnetic fields (EMF) are widely used in musculoskeletal disorders. There are indications that EMF might also be effective in the treatment of osteoporosis. To justify clinical follow-up experiments, we examined the effects of EMF on bone micro-architectural changes in osteoporotic and healthy rats. Moreover, we tested the effects of EMF on fracture healing.

Objectives

The effects of disease progression and common tendinopathy treatments on the tissue characteristics of human rotator cuff tendons have not previously been evaluated in detail owing to a lack of suitable sampling techniques. This study evaluated the structural characteristics of torn human supraspinatus tendons across the full disease spectrum, and the short-term effects of subacromial corticosteroid injections (SCIs) and subacromial decompression (SAD) surgery on these structural characteristics.

Objectives

We aimed to examine the characteristics of deep venous flow in the leg in a cast and the effects of a wearable neuromuscular stimulator (geko; FirstKind Ltd) and also to explore the participants’ tolerance of the stimulator.

This study investigates the use of porous biphasic ceramics as graft extenders in impaction grafting of the femur during revision hip surgery.

Impaction grafting of the femur was performed in four groups of sheep. Group one received pure allograft, group two 50% allograft and 50% BoneSave, group three 50% allograft and 50% BoneSave type 2 and group four 10% allograft and 90% BoneSave as the graft material. Function was assessed using an index of pre- and post-operative peak vertical ground reaction force ratios. Changes in bone mineral density were measured by dual energy X ray absorptiometry (DEXA) scanning. Loosening and subsidence were assessed radiographically and by histological examination of the explanted specimens.

There was no statistically significant difference between the four groups after 18 months of unrestricted functional loading for all outcome measures.

Aspiration arthrography using an iodinated contrast medium is a useful tool for the investigation of septic or aseptic loosening of arthroplasties and of septic arthritis. Previously, the contrast media have been thought to cause false negative results in cultures when present in aspirated samples of synovial fluid, probably because free iodine is bactericidal, but reports have been inconclusive.

We examined the influence of the older, high osmolar contrast agents and the low osmolar media used currently on the growth of ten different micro-organisms capable of causing deep infection around a prosthesis. Five media were tested, using a disc diffusion technique and a time-killing curve method in which high and low inocula of micro-organisms were incubated in undiluted media. The only bactericidal effects were found with low inocula of Escherichia coli and Pseudomonas aeruginosa in ioxithalamate, one of the older ionic media.

The low and iso-osmolar iodinated contrast media used currently do not impede culture. Future study must assess other causes of false negative cultures of synovial fluid and new developments in enhancing microbial recovery from aspirated samples.

Intra-articular punctures and injections are performed routinely on patients with injuries to and chronic diseases of joints, to release an effusion or haemarthrosis, or to inject drugs. The purpose of this study was to investigate the accuracy of placement of the needle during this procedure.

A total of 76 cadaver acromioclavicular joints were injected with a solution containing methyl blue and subsequently dissected to distinguish intra- from peri-articular injection. In order to assess the importance of experience in achieving accurate placement, half of the injections were performed by an inexperienced resident and half by a skilled specialist. The specialist injected a further 20 cadaver acromioclavicular joints with the aid of an image intensifier. The overall frequency of peri-articular injection was much higher than expected at 43% (33 of 76) overall, with 42% (16 of 38) by the specialist and 45% (17 of 38) by the resident. The specialist entered the joint in all 20 cases when using the image intensifier.

Correct positioning of the needle in the joint should be facilitated by fluoroscopy, thereby guaranteeing an intra-articular injection.

We have studied the effects of bupivacaine on human and bovine articular chondrocytes in vitro. Time-lapse confocal microscopy of human articular chondrocytes showed > 95% cellular death after exposure to 0.5% bupivacaine for 30 minutes. Human and bovine chondrocytes exposed to 0.25% bupivacaine had a time-dependent reduction in viability, with longer exposure times resulting in higher cytotoxicity. Cellular death continued even after removal of 0.25% bupivacaine. After exposure to 0.25% bupivacaine for 15 minutes, flow cytometry showed bovine chondrocyte viability to be 41% of saline control after seven days. After exposure to 0.125% bupivacaine for up to 60 minutes, the viability of both bovine and human chondrocytes was similar to that of control groups.

These data show that prolonged exposure 0.5% and 0.25% bupivacaine solutions are potentially chondrotoxic.

The stress response to trauma is the summation of the physiological response to the injury (the ‘first hit’) and by the response to any on-going physiological disturbance or subsequent trauma surgery (the ‘second hit’).

Our animal model was developed in order to allow the study of each of these components of the stress response to major trauma. High-energy, comminuted fracture of the long bones and severe soft-tissue injuries in this model resulted in a significant tropotropic (depressor) cardiovascular response, transcardiac embolism of medullary contents and activation of the coagulation system. Subsequent stabilisation of the fractures using intramedullary nails did not significantly exacerbate any of these responses.

Little is known about the increase in length of tendons in postnatal life or of their response to limb lengthening procedures. A study was carried out in ten young and nine adult rabbits in which the tibia was lengthened by 20% at two rates 0.8 mm/day and 1.6 mm/day.

The tendon of the flexor digitorum longus (FDL) muscle showed a significant increase in length in response to lengthening of the tibia. The young rabbits exhibited a significantly higher increase in length in the FDL tendon compared with the adults. There was no difference in the amount of lengthening of the FDL tendon at the different rates. Of the increase in length which occurred, 77% was in the proximal half of the tendon.

This investigation demonstrated that tendons have the ability to lengthen during limb distraction. This occurred to a greater extent in the young who showed a higher proliferative response, suggesting that there may be less need for formal tendon lengthening in young children.

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

The reduced stability of hydroxyapatite (HA)-coated implants in osteopenic conditions is considered to be a major problem. We therefore developed a model of a boosted cementless implantation in osteopenic rats.

Twelve-week-old rats were either ovariectomised (OVX) or sham-operated (SO), and after 24 weeks plain or HA-coated implants were inserted. They were treated with either a prostaglandin EP4 receptor agonist (ONO-4819) or saline for one month.

The EP4 agonist considerably improved the osteoporosis in the OVX group. Ultrastructural analysis and mechanical testing showed an improvement in the implant-bone attachment in the HA-coated implants, which was further enhanced by the EP4 agonist. Although the stability of the HA-coated implants in the saline-treated OVX rats was less than in the SO normal rats, the administration of the EP4 agonist significantly compensated for this shortage. Our results showed that the osteogenic effect of the EP4 agonist augmented the osteoconductivity of HA and significantly improved the stability of the implant-bone attachment in the osteoporotic rat model.

We used a canine intercalary bone defect model to determine the effects of recombinant human osteogenic protein 1 (rhOP-1) on allograft incorporation. The allograft was treated with an implant made up of rhOP-1 and type I collagen or with type I collagen alone.

Radiographic analysis showed an increased volume of periosteal callus in both test groups compared with the control group at weeks 4, 6, 8 and 10. Mechanical testing after 12 weeks revealed increased maximal torque and stiffness in the rhOP-1 treated groups compared with the control group.

These results indicate a benefit from the use of an rhOP-1 implant in the healing of bone allografts. The effect was independent of the position of the implant. There may be a beneficial clinical application for this treatment.

Strains applied to bone can stimulate its development and adaptation. High strains and rates of strain are thought to be osteogenic, but the specific dose response relationship is not known. In vivo human strain measurements have been performed in the tibia to try to identify optimal bone strengthening exercises for this bone, but no measurements have been performed in the distal radial metaphysis, the most frequent site of osteoporotic fractures. Using a strain gauged bone staple, in vivo dorsal metaphyseal radial strains and rates of strain were measured in ten female patients during activities of daily living, standard exercises and falls on extended hands. Push-ups and falling resulted in the largest compression strains (median 1345 to 3146 με, equivalent to a 0.1345% to 0.3146% length change) and falling exercises in the largest strain rates (18 582 to 45 954 με/s). On the basis of their high strain and/or strain rates these or variations of these exercises may be appropriate for distal radial metaphyseal bone strengthening.