The purpose of this scoping review was to identify possible chondrotoxic effects caused by drugs usually used for intra-articular injections. PubMed, Scopus, Web of Science and Cochrane were searched. Inclusion criteria required randomized controlled trials written in English that evaluate the toxic effect that damages the cartilage. The literature search resulted in 185 unique articles. 133 full-text articles were screened for inclusion, of which 65 were included. Corticosteroids, with the exception of triamcinolone, along with local anaesthetics, potentially excluding ropivacaine and liposomal bupivacaine, and nonsteroidal anti-inflammatory drugs, exhibited insufficient safety profiles to warrant casual use in clinical settings. Hyaluronic acid, on the other hand, appears to demonstrate safety while also mitigating risks associated with concurrent compounds, thereby facilitating therapeutic combinations. Additionally, there remains a paucity of data regarding platelet-rich plasma, necessitating further evaluation of its potential efficacy and safety. Overall, it seems that results are significantly influenced by the dosage and frequency of injections administered, observed in both human and animal studies.

Introduction A constant infusion of local anesthetics through pain pumps has been shown to cause chondrolysis. However, there is no general consensus regarding the safety of a single intra-articular injection of local anesthetics. In this experimental study, we examined the rat cartilage for possible histological effects after a single intra-articular administration of lidocaine or ropivacaine. Material and methods Thirty-two male Sprague-Dawley rats, weighing 250-300 grams, were divided into two groups of 16 each. We injected 0.1 ml of either lidocaine 2% (20 mg/ml) or ropivacaine 0.75% (7.5 mg/ml) into the left knee of the rats. The right knee in both groups was used as a control, and an equal amount of normal saline was injected. Each group was further divided into subgroups of four, which were euthanized after one, seven, 21, and 60 days after the initial injection. Knees were excised and prepared for histopathological analysis. A modified version of the Mankin score was used for cartilage damage evaluation. Results No difference regarding cartilage damage was detected after the examination under light microscopy between lidocaine, ropivacaine, and placebo in all specimens. Time elapsed since the initial injection did not affect the results at any time point. Conclusion A single intra-articular injection of local anesthetic did not induce any histological changes in the rat cartilage. Further research is needed to demonstrate the safety of humans.

UNASSIGNED: Intraarticular corticosteroid injections (ICIs) are widely used to treat foot and ankle conditions. Although laboratory studies indicate certain corticosteroids and local anesthetics used in ICIs are associated with chondrotoxic effects, and selected agents such as ropivacaine and triamcinolone may have less of these features, clinical evidence is lacking. We aimed to identify the patterns of drug selection, perceptions of injectate chondrotoxicity, and rationale for medication choice among surgeons in the American Orthopaedic Foot & Ankle Society (AOFAS).
UNASSIGNED: An e-survey including demographics, practice patterns, and rationale was disseminated to 2011 AOFAS members. Frequencies and percentages were calculated for demographic data, anesthetic and steroid choice, rationale for injectate choice, and perception of chondrotoxicity. Bivariate analysis was used to identify practice patterns significantly associated with perceptions of injectate risk and rationale.
UNASSIGNED: In total, 387 surveys were completed. Lidocaine and triamcinolone were the most common anesthetic and corticosteroid used (51.2% and 39.3%, respectively). Less than half of respondents felt corticosteroids or local anesthetics bear risk of chondrotoxicity. Respondents agreeing that corticosteroids are chondrotoxic were more likely to use triamcinolone (P = .037). Respondents agreeing local anesthetics risk chondrotoxicity were less likely to use lidocaine (P = .023). Respondents choosing a local anesthetic based on literature were more likely to use ropivacaine (P < .001).
UNASSIGNED: Corticosteroid and local anesthetic use in ICIs varied greatly. Rationale for ICI formulation was also variable, as the clinical implications are largely unknown. Those who recognized potential chondrotoxicity and who chose based on literature were more likely to choose ropivacaine and triamcinolone, as reflected in the basic science literature. Further clinical studies are needed to establish guidelines that shape foot and ankle ICI practices based on scientific evidence and reduce the variation identified by this study.
UNASSIGNED: Level IV, cross-sectional survey study.

UNASSIGNED: Intra-articular antibiotics have been proposed as a treatment for septic arthritis to allow for high local concentrations without subjecting a patient to the toxicity/side effects of systemic therapy. However, there is concern for chondrotoxicity with intra-articular use of these solutions in high concentrations. The purpose of this systematic review was to evaluate the intra-articular use of antibiotics and antiseptic solutions, and to determine their association with chondrolysis following in vitro or in vivo administration.
UNASSIGNED: A systematic review was conducted following PRISMA guidelines through PubMed, Clinical Key, OVID, and Google Scholar. Studies in English were included if they evaluated for chondrotoxicity following antibiotic exposure.
UNASSIGNED: The initial search resulted in 228 studies, with 36 studies meeting criteria. These 36 studies included manuscripts that studied 24 different agents. Overall, 7 of the 24 (29%) agents were non-chondrotoxic: minocycline, tetracycline, chloramphenicol, teicoplanin, pefloxacin, linezolid, polymyxin-bacitracin. Eight (33%) agents had inconsistent results: doxycycline, ceftriaxone, gentamicin, vancomycin, ciprofloxacin, ofloxacin, chlorhexidine, and povidone iodine. Chondrotoxicity was evident with 9 (38%) agents, all of which were also dose-dependent chondrotoxic based on reported estimated half maximal inhibitory concentrations (est. IC50): amikacin (est. IC50 = 0.31-2.74 mg/mL), neomycin (0.82), cefazolin (1.67-3.95), ceftazidime (3.16-3.59), ampicillin-sulbactam (8.64 - >25), penicillin (11.61), amoxicillin (14.01), imipenem (>25), and tobramycin (>25). Additionally, chondroprotective effects of doxycycline and minocycline were reported.
UNASSIGNED: This systematic review identified agents that may be used in the treatment of septic arthritis. Nine agents should be avoided due to their dose-dependent chondrotoxic effects. Further studies are needed to clarify the safety of these medications for human intra-articular use.

Studies have revealed that vancomycin soaking of the anterior cruciate ligament (ACL) graft can drastically reduce the incidence of postoperative infections after ACL reconstruction. However, it remains unknown whether the chondrotoxic threshold of vancomycin in synovial fluid is exceeded during this process. Several studies investigated the chondrotoxic properties of vancomycin in in vitro experiments and described a concentration of 1000 µg/mL as the critical threshold.
The purpose of the study was to measure the vancomycin concentration in synovial fluid after ACL reconstruction with vancomycin-soaked autografts. It was hypothesized that intra-articular vancomycin concentrations in the synovial fluid would not reach the chondrotoxic threshold of 1000 µg/mL after vancomycin soaking of autologous semitendinosus tendon and soft tissue quadriceps tendon grafts for ACL reconstruction.
Cohort study; Level of evidence, 3.
The study enrolled 10 patients undergoing ACL reconstruction using 4-strand semitendinosus tendon autografts and 10 patients undergoing ACL reconstruction using soft tissue quadriceps tendon autografts. Before implantation, each harvested graft was intraoperatively wrapped in gauze swabs that had been soaked in a 5-mg/mL vancomycin solution. After wound closure, an aspirate of 5 mL of synovial fluid was taken from each patient. The vancomycin concentration of the aspirate was analyzed using high-performance liquid chromatography-tandem mass spectrometry. Spearman rho correlation coefficients were used to identify relationships between the parameters, and the t test was used to test for differences between graft types. A P value of <.05 was considered statistically significant.
The study included 20 patients (14 women and 6 men; age, 29.35 ± 11.3 years). The mean vancomycin concentration measured in the synovial fluid was 23.23 ± 21.68 µg/mL, with a minimum concentration of 2.32 µg/mL and a maximum concentration of 71.56 µg/mL. No significant difference was found between the 2 graft types (P = .911). Significant positive correlation (r = 0.644; P < .05) was observed only between the vancomycin concentration and the mean duration from initiation of vancomycin soaking of semitendinosus tendon grafts to implantation (13.4 ± 6 minutes). No correlations were observed between the vancomycin concentration and the duration from implantation to fluid aspiration or between the vancomycin concentration and the graft diameter (median, 8.5 mm; range, 6.0-10.0 mm) for both graft types.
Chondrotoxic vancomycin concentrations ≥1000 µg/mL were not reached in any aspiration of synovial fluid after ACL reconstruction using soft tissue autografts that were intraoperatively soaked in a 5-mg/mL vancomycin solution. Against the backdrop of multiple studies that showed significantly reduced infection rates after ACL reconstruction when vancomycin soaking was used, this study suggests that the chondrotoxic properties of this method are negligible because of its submarginal intra-articular concentrations.

Bupivacaine, levobupivacaine and ropivacaine are potent, long acting, amide-type local anesthetics that have several clinical applications including intra-articular administration. The objectives of this study were to evaluate their in vitro effects on cell viability and caspase activity to elucidate whether they activate the extrinsic or intrinsic pathways of apoptosis in canine articular chondrocytes. Chondrocytes in monolayer culture were treated with culture medium as the control, or with 0.062% (0.62 mg/mL) bupivacaine, 0.062% levobupivacaine, and 0.062% ropivacaine for 24 hr. Cell viability was evaluated using the live/dead, 3-(4,5-dimehylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), and Cell Counting Kit-8 (CCK-8) assays. Evaluation of caspase-3, caspase-8, and caspase-9 activity was performed using colorimetric assays. The MTT and CCK-8 assays were used to evaluate the effect of caspase inhibitors on local anesthetic chondrotoxicity. All three local anesthetics decreased chondrocyte viability after 24 hr (P<0.001). Apoptosis was induced through both the extrinsic and intrinsic pathways. Bupivacaine increased caspase-3, caspase-8, and caspase-9 activity (P<0.001). Levobupivacaine increased caspase-3 (P=0.03) while ropivacaine did not significantly upregulate activity for all three caspases. Caspase inhibition did not suppress bupivacaine chondrotoxicity whereas inhibition of caspase-8 and caspase-9 decreased ropivacaine chondrotoxicity and mildly attenuated levobupivacaine chondrotoxicity. In summary, the level of chondrotoxicity, the type of caspase activated, the level of caspase activation, and the response to caspase inhibitors was dependent on the type of local anesthetic. Therefore, ropivacaine may be a safer choice for intra-articular administration compared to levobupivacaine and bupivacaine.

UNASSIGNED: Local anesthetics are commonly used in surgical procedures to control pain in patients. Whilst the cardiotoxicity and neurotoxicity of local anesthetics have received much attention, the cytotoxicity they exert against bone, joint, and muscle tissues has yet to be well recognized.
UNASSIGNED: This review aimed to raise awareness regarding how local anesthetics may cause tissue damage and provide a deeper understanding of the mechanisms of local anesthetic-induced cytotoxicity. We summarized the latest progress on the cytotoxicity of local anesthetics and the underlying mechanisms and discussed potential strategies to reduce it.
UNASSIGNED: We found that the toxic effects of local anesthetics on bone, joint, and muscle tissues were time- and concentration-dependent in vitro. Local anesthetics induced apoptosis, necrosis, and autophagy through specific cellular pathways. Altogether, this review indicates that toxicity of local anesthetics may be avoided by rationally selecting the appropriate anesthetic, limiting the total amount, and determining the lowest effective concentration and duration.

Considering the potential chondrotoxic effects of lidocaine, this retrospective study aimed to examine whether ultrasound-guided hydrodilatation without concurrent lidocaine infusion can still provide comparable treatment benefits for patients with adhesive capsulitis (AC). Outpatient data from 104 eligible AC patients who received ultrasound-guided hydrodilatation between May 2016 and April 2021 were reviewed. A total of 59 patients received hydrodilatation with diluted corticosteroid only, while 45 patients received treatment with mixed, diluted corticosteroid and 1% lidocaine. The overall treatment outcome was documented as the percentage of clinical improvement, ranging from 0% to 100% compared to baseline, and it was ranked into poor, moderate and good treatment outcomes. The results show no significant group-wise difference in demographics, overall treatment outcome, and number of hydrodilatations, while most patients showed moderate and good treatment outcomes. Patients with lidocaine infusion did not show greater treatment benefit. Our results suggest that ultrasound-guided hydrodilatation without concurrent lidocaine infusion can still deliver good treatment benefits for AC patients, and the findings are supportive of a modified approach toward careful intra-articular local anesthetic use during management of AC in the primary care setting.

The ecotoxicological risk to vertebrates posed by zinc oxide nanoparticles (ZnO NPs) is still poorly understood, especially in animals with a biphasic life cycle, which have aquatic and terrestrial phases, such as amphibians. In the present study, we investigated whether acute exposure (7 days) to ZnO NPs and zinc chloride (ZnCl2) at three environmentally relevant concentrations (0.1, 1.0, and 10 mg L-1) induces changes in the morphology, chondrocranium, and behavior of the tadpoles of Lithobates catesbeianus (Anura: Ranidae). Tadpoles exposed to both forms of Zn did not undergo any morphological or behavioral changes at the lowest concentrations (0.1 and 1.0 mg L-1). However, the animals exposed to the highest concentration (10 mg L-1) lacked oral disc structures, were smaller in size, had a longer tail, and presented changes in the position and coiling of the intestine and malformations of the chondrocranium in comparison with the control group. This indicates that ZnO NPs and ZnCl2 altered the development of the tadpoles, causing delays in their metamorphosis and even reducing individual fitness. The tadpoles exposed to both forms of Zn at 10 mg L-1 also had reduced mobility, especially in the presence of conspecifics. Based on these findings, we emphasize the importance of studying morphological, skeletal, and behavioral biomarkers to evaluate the toxic effects of metal-based nanoparticles in amphibians.

Fluoroquinolone (FQ) antibacterials have drawn heightened attention from various international regulatory agencies due to their class-specific side effects. Levonadifloxacin is a novel broad spectrum benzoquinolizine FQ active against methicillin-resistant Staphyloccocus aureus (MRSA). Owing to FQ-associated safety concerns, extensive preclinical safety pharmacology (central nervous system and cardiac safety) and toxicology studies (subacute repeat-dose toxicity, genotoxicity, phototoxicity and chondrotoxicity) of levonadifloxacin were performed at relatively high doses. Intravenous (IV) and oral studies were conducted using WCK 771 (l-arginine salt of levonadifloxacin) and WCK 2349 (l-alanine ester prodrug of levonadifloxacin), respectively. Safety pharmacology studies following single dose revealed no adverse effects on central nervous system (including seizure) in mice and cardiovascular system (hERG and monkey telemetry). In repeat-dose toxicity studies, except for IV bolus dosing related effects in rat (hyperactivity, mild convulsion, polypnoea and injection site irritation) and dog (emesis and salivation), no other adverse findings limiting the dosing duration were observed. No major biochemical, haematological, gross or histopathological changes suggestive of damage to vital organs were observed in either WCK 771- or WCK 2349-treated groups. WCK 771 and WCK 2349 were found to be nongenotoxic; however, they showed weak phototoxicity that was comparable with levofloxacin. WCK 771 showed chondrotoxicity in the Beagle dog pups on repeat-dose administration; however, the severity level was lower than ofloxacin. Overall, preclinical safety studies helped establish wider safety margin for WCK 771 and WCK 2349 that supports administration of higher therapeutic doses in humans by both IV and oral routes, thereby enabling safe anti-MRSA treatment.