Objectives. Triamcinolone acetonide (TA) is widely used for the treatment of rotator cuff injury because of its anti-inflammatory properties. However, TA can also produce deleterious effects such as tendon degeneration or rupture. These harmful effects could be prevented by the addition of platelet-rich plasma (PRP), however, the anti-inflammatory and anti-degenerative effects of the combined use of TA and PRP have not yet been made clear. The objective of this study was to determine how the combination of TA and PRP might influence the inflammation and degeneration of the rotator cuff by examining rotator cuff-derived cells induced by interleukin (IL)-1ß. Methods. Rotator cuff-derived cells were seeded under inflammatory stimulation conditions (with serum-free medium with 1 ng/ml IL-1ß for three hours), and then cultured in different media: serum-free (control group), serum-free + TA (0.1mg/ml) (TA group), serum-free + 10% PRP (PRP group), and serum-free + TA (0.1mg/ml) + 10% PRP (TA+PRP group). Cell morphology, cell viability, and expression of inflammatory and degenerative mediators were assessed. Results. Exposure to TA significantly decreased cell viability and changed the cell morphology; these effects were prevented by the simultaneous administration of PRP. Compared with the control group, expression levels of inflammatory genes and reactive oxygen species production were reduced in the TA, PRP, and TA+PRP groups. PRP significantly decreased the expression levels of degenerative marker genes. Conclusions. The combination of TA plus PRP exerts anti-inflammatory and anti-degenerative effects on rotator cuff-derived cells stimulated by IL-1ß. This combination has the potential to relieve the symptoms of rotator cuff injury. Cite this article: T. Muto, T. Kokubu, Y. Mifune, A. Inui, R. Sakata, Y. Harada, F. Takase, M. Kurosaka. Effects of platelet-rich plasma and triamcinolone acetonide on interleukin-1ß-stimulated human rotator cuff-derived cells. Bone Joint Res 2016;5:602–609. DOI: 10.1302/2046-3758.512.2000582

Objectives. To investigate the appropriate dose and interval for the administration of triamcinolone acetonide (TA) in treating tendinopathy to avoid adverse effects such as tendon degeneration and rupture. Methods. Human rotator cuff-derived cells were cultured using three media: regular medium (control), regular medium with 0.1 mg/mL of TA (low TA group), and with 1.0 mg/mL of TA (high TA group). The cell morphology, apoptosis, and viability were assessed at designated time points. Results. In the low TA group, the cells became flattened and polygonal at seven days then returned to normal at 21 days. The cell apoptosis ratio and messenger ribonucleic acid expression of caspase-3, 7, 8, and 9 increased, and viability was reduced in the low and high groups at seven days. In the low TA group, apoptosis and viability returned to normal at 21 days, however, in the high TA group, the cell morphology, apoptosis ratio, caspase-3, 7, 8, and 9 and viability did not return by day 21. Re-administration was performed in the low TA group at 7-, 14-, and 21-day intervals, and cell viability did not return to the control level at the 7- and 14-day intervals. Conclusion. A 0.1 mg/mL dose of TA temporarily decreased cell viability and increased cell apoptosis, which was recovered at 21 days, however, 1 mg/mL of TA caused irreversible damage to cell morphology and viability. An interval > three weeks was needed to safely re-administer TA. These findings may help determine the appropriate dose and interval for TA injection therapy. Cite this article: Bone Joint Res 2014;3:328–34

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

This was a double-blind randomised controlled study. The objective of this study was to determine the cause of post-injection pain after peri-articular steroid injection. Approval for this study was granted by the hospital’s Ethics Committee. Selection criteria included all patients undergoing a peri-articular injection under the care of the senior author. Patients who elected to be in this study gave their consent following a detailed explanation of the study and provision of a patient information leaflet. The enrolled patients were randomised into one of two groups. Group A received a standard triamcinolone acetonide injection mixed with bupivicaine. Group B patients received triamcinolone acetonide without the preservative part of the drug and bupivicaine. Both the patient and the surgeon were unaware which group the patient was selected to be in. Patients’ scores were recorded using visual analogue scales and pain severity scores prior to injection and 4 days following injection. Inflammatory signs were also recorded at 4 days post-procedure. A total of 52 patients were enrolled. Pain scores reduced by 46% in group A and 43% in group B. Inflammatory signs occurred in 26% less cases when group B was compared with group A, however this was not statistically significant

In osteoarthritis, chondrocytes acquire a hypertrophic phenotype that contributes to matrix degradation. Inflammation is proposed as trigger for the shift to a hypertrophic phenotype. Using in vitro culture of human chondrocytes and cartilage explants we could not find evidence for a role of inflammatory signalling activation. We found, however, that tissue repair macrophages may contribute to the onset of hypertrophy (doi: 10.1177/19476035211021907) Intra-articularly injected triamcinolone acetonide to inhibit inflammation in a murine model of collagenase-induced osteoarthritis, increased synovial macrophage numbers and osteophytosis, confirming the role of macrophages in chondrocyte hypertrophy occurring in osteophyte formation (doi: 10.1111/bph.15780). In search of targets to inhibit chondrocyte hypertrophy, we combined existing microarray data of different cartilage layers of murine growth plate and murine articular cartilage after induction of collagenase-induced osteoarthritis. We identified common differentially expressed genes and selected those known to be associated to inflammation. This revealed EPHA2, a tyrosine kinase receptor, as a new target. Using in silico, in vitro and in vivo models we demonstrated that inhibition of EPHA2 might be a promising treatment for osteoarthritis. Recently, single cell RNA-seq. has revealed detailed information about different populations of chondrocytes in articular cartilage during osteoarthritis. We re-analysed a published scRNA-seq data set of healthy and osteoarthritic cartilage to obtain the differentially expressed genes in the population of hypertrophic chondrocytes compared to the other chondrocytes, applied pathway analyses and then used drug databases to search for upstream inhibitors of these pathways. This drug repurposing approach led to the selection of 6 drugs that were screened and tested using several in vitro models with human chondrocytes and cartilage explants. In this lecture I will present this sequence of studies to highlight different approaches and models that can be used in the quest for a disease modifying drug for osteoarthritis

Introduction. Osteoarthritis (OA) often results from joint misloading, which affects chondrocyte calcium signaling through mechano-sensitive receptors such as Piezo1, -2, and TRPV4. Activation of Piezo1, especially under inflammatory conditions, can trigger premature chondrocyte apoptosis. Intra-articular glucocorticoid therapy, while beneficial against inflammation and pain in osteoarthritis, may induce oxidative stress and chondrotoxicity at higher doses. This study aims to assess the effects of glucocorticoids, particularly triamcinolone, on chondrocyte elasticity and mechanosignaling. Method. Chondrocytes isolated from articular condyles obtained from patients undergoing knee replacement surgery (n= 5) were cultured for 7 days in triamcinolone acetonide (TA) at different concentrations (0.2µM – 2mM). Cytoskeletal changes were assessed by F-actin labeling. Cell elasticity was measured using atomic force microscopy (AFM). Labeling cells (n=6 patients) with the calcium-sensitive dye (Fluo-4) enabled monitoring changes in intracellular calcium fluorescence intensity during guided single-cell mechanical indentation (500 nN) by AFM. Result. Cell exposure to 2 mM TA led to cell death and crystallization of TA in the cell culture media. However, the concentration of TA for intra-articular application is 46 times higher at 92.1 mM (40 mg/ml). The maximal pharmacological effect on viable cells was observed at 0.2 mM. AFM results showed a significant decrease of elasticity (p<0.001), alongside significantly higher calcium intensities both prior to and during mechanical stimulation in the TA-treated samples (p<0.05). Conclusion. Administration of TA significantly impacts the mechanical properties of chondrocytes, reducing cellular elasticity while simultaneously enhancing calcium-dependent mechanosensitivity. This data suggests a correlation between glucocorticoid-induced changes in cell elasticity and cell mechanosensitivity. Finding ways to minimize the effect of glucocorticoids on cell mechanosensitivity could help to make future therapies safer and reduce side effects

Joint injuries often result in inflammation and cartilage defects. When inflamed, the synovium secretes factors that prevent successful cartilage repair by inhibiting chondrogenic differentiation of progenitor cells. In particular the pro-inflammatory macrophages in the synovium are indicated to contribute to this anti-chondrogenic effect. Thus, we aimed to counteract the anti-chondrogenic effect of inflamed synovium by modulating synovial inflammation and its macrophages. Synovium tissue obtained from osteoarthritic patients undergoing a total knee replacement was cut into explants and cultured for 72 hours +/− 1 µM of the anti-inflammatory drug triamcinolone acetonide (TAA) (Sigma Aldrich). TAA significantly decreased gene expression of TNFA, IL1β and IL6, and increased expression of CCL18, IL1RA in synovial explants (all with p < 0.001). On the other hand, TAA significantly decreased the percentages of pro-inflammatory CD14+/CD80+ and CD14+/CD86+ macrophages in the synovium (both p < 0.001) as assessed by flow cytometry analyses. The percentages of anti-inflammatory CD14+/CD163+ macrophages, is significantly increased (p < 0.001) in TAA treated synovium. Conditioned medium (CM) from synovium explants downregulated the gene expression of cartilage matrix components collagen type-2 and aggrecan expression in chondrogenic MSCs. This chondrogenesis inhibiting effect was reduced by treating synovium with TAA during the production of the CM. Our findings indicate that reducing synovial inflammation might improve the joint environment for better cartilage repair, possibly by modulation of macrophage phenotypes

Local infiltration analgesia (LIA) is promoted as an effective treatment modality for pain control after total knee arthroplasty (TKA) (1). A mixture of drugs is used to provide a multimodal analgesic effect. Previous studies reported that the use of these drugs is safe. After we carefully implemented a LIA study protocol in our practice, concerns raised about patient safety with probably higher infection rates. This forced us to perform an interim analysis after the first 58 cases. 58 patients underwent a unilateral TKA with a standardised LIA protocol (2), which consisted of a mixture of ropivacaine, epinephrine, and triamcinolone acetonide. Complications, knee function and patient satisfaction scores were prospectively recorded during regular outpatient control. Four patients (6.9%) presented with signs of periprosthetic joint infection (PJI) within two months after surgery. Baseline characteristics were similar between the infected and non infected group. All infections were treated with debridement and retention, and antimicrobial treatment was started. One patient who suffered an infection died during followup. At two years followup all implants could be retained. Knee function and KSS score were acceptable for the patients who suffered PJI. There is no consensus on the combination of drugs used for LIA. The application of corticosteroids in LIA is reported to be safe (3), but arguable results about the injection of local corticosteroids around knee arthroplasty surgery in the past have raised suspicion in literature (4). Combined with our unacceptable high rate of PJI, we believe that the current body of evidence, with small heterogeneous series, does not support the safe use of corticosteroids in LIA

Introduction: Intra-articular steroid injection has been widely used for relief of pain in osteoarthritis. Recent studies show an increasing rate of infection in these patients following hip arthroplasty. We have reviewed our cohort of patients to see if they are susceptible to higher infection rate. Methods: We reviewed a cohort of 167 consecutive hips that had at least one injection with a 40mg triamcinolone acetonide and 4ml 0.5% bupivacaine mixture to relieve the symptoms of hip osteoarthritis or to clarify a diagnosis of hip arthritis between January 1997 and November 2004 were reviewed. A total of 37 hips (36 patients) that subsequently proceeded to have a total hip arthroplasty were selected as our study group. There was a minimum of a one-year follow up. Results: The rate of infection in our initial cohort of patients following a hip injection was 0.60% (1 hip) which resulted in repeated washouts and a subsequent total hip arthroplasty with a good outcome. On review of the 37 hips, one was revised due to a deep infection secondary to staphylococcus epidermidis. Four were revised for continued instability and pain with no evidence of infection either prior to or during revision. When deep infection is taken as an endpoint, cumulative survival at 7.5 years is 0.968 (95% confidence interval of 1 to 0.905). The total survivorship of this cohort if all revisions are included is 0.852 at 7.5 years (95% confidence interval of 0.730 to 0.974). The revision rate due to a deep infection in our study is 2.7%. Discussion: We conclude that patients who have a total hip arthroplasty after a hip injection do not have an adversely high rate of deep infection

Intra-articular steroid injection has been widely used for relief of pain in Osteoarthritis. Recent studies show an increasing rate of infection in these patients following hip arthroplasty. We have reviewed our cohort of patients to see if they are susceptible to higher infection rate. We reviewed a cohort of 167 consecutive hips that had at least one injection with a 40mg triamcinolone acetonide and 4ml 0.5% bupivacaine mixture to relieve the symptoms of hip osteoarthritis or to clarify a diagnosis of hip arthritis between January 1997 and Novem-ber 2004 were reviewed. A total of 37 hips (36 patients) that subsequently proceeded to have a total hip arthroplasty were selected as our study group. There was a minimum of a one-year follow up. The rate of infection in our initial cohort of patients following a hip injection was 0.60% (1 hip) which resulted in repeated washouts and a subsequent total hip arthroplasty with a good outcome. On review of the 37 hips, one was revised due to a deep infection secondary to staphylococcus epidermidis. Four were revised for continued instability and pain with no evidence of infection either prior to or during revision. When deep infection is taken as an endpoint, cumulative survival at 7.5 years is 0.968 (95% confidence interval of 1 to 0.905). The total survivorship of this cohort if all revisions are included is 0.852 at 7.5 years (95% confidence interval of 0.730 to 0.974). The revision rate due to a deep infection in our study is 2.7%. We conclude that patients who have a total hip arthroplasty after a hip injection do not have an adversely high rate of deep infection

We describe results of a new ‘two needle technique’ of selective nerve root blocks done through posterior triangle of neck in the management of cervical radiculopathy with 2 year results. Methods: Patients presenting with cervical radiculopathy were evaluated clinically and radiologically and were initially managed with supervised physiotherapy, analgesics and rest. Selective cervical nerve root block was offered to the patients, who did not respond to conservative management. The procedure was performed as a day case, under local anesthesia, with image intensifier guidance, using ‘two needle technique’. A thinner needle is rail-roaded through the lumen of large diameter guide needle to reach the target nerve root foramen and a mixture of Bupivacaine and Triamcinolone acetonide is injected. The outcome was measured using visual analogue score (VAS) and neck disability index (NDI) done on the day of the procedure and compared to the scores at 3 months and 1 year after the procedure. Results: Outcome in 30 patients who underwent this procedure over three years’ period is presented. Average Visual Analogue Score was 7.36 (range 6 – 10) before the intervention, which improved to 2.27 (range 0 – 7) at 3 months and 1.9 (range 0 – 4) at 1 year. The average Neck Disability Index score prior to intervention was 66.87 (range 44 to 82), which improved to 31.67 (range 18 – 66) at 3 months and 30.44 (range 20 – 48) at 1 year. There were no major complications noted. We conclude that selective cervical nerve root block using ‘two-needle technique’ is safe and reproducible. The therapeutic effect achieved is long lasting, making this procedure a good alternative to surgical management in patients with cervical radiculopathy who do not respond to conservative management

Osteoarthritis (OA) is an important cause of pain, disability and economic loss in humans, and is similarly important in the horse. Recent knowledge on post-traumatic OA has suggested opportunities for early intervention, but it is difficult to identify the appropriate time of these interventions. The horse provides two useful mechanisms to answer these questions: 1) extensive experience with clinical OA in horses; and 2) use of a consistently predictable model of OA that can help study early pathobiological events, define targets for therapeutic intervention and then test these putative therapies. This paper summarises the syndromes of clinical OA in horses including pathogenesis, diagnosis and treatment, and details controlled studies of various treatment options using an equine model of clinical OA.

The October 2015 Knee Roundup360 looks at: Allergy and outcome in arthroplasty; Physiotherapy and drains not such a bad combination?; Another nail in the coffin for arthroscopists?; Graft precondition hocus pocus; Extended dose steroids in knee arthritis?; Indolent peri-prosthetic infection; Computer modelling and medial knee arthritis

The December 2014 Shoulder & Elbow Roundup³⁶⁰ looks at: cuff tears and plexus injury;

corticosteroids and physiotherapy in SAI; diabetes and elbow arthroplasty; distal biceps tendon repairs; shockwave therapy in frozen shoulder; hydrodilation and steroids for adhesive capsulitis; just what do our patients read?; and what happens to that stable radial head fracture?