Background: The administration of amide-type local anesthetics to cartilaginous tissues has revealed potential chondrotoxicity.
Purpose: This study evaluated whether administration of single doses of 1% lidocaine, 0.25% bupivacaine, and 0.5% ropivacaine resulted in decreased chondrocyte viability or cartilage matrix degradation in vitro.
Study Design: Controlled laboratory study.
Methods: Monolayer human chondrocytes and intact cartilage samples were cultured for 1 week in media. Each drug was delivered in a custom bioreactor over its clinical duration of action. A Live/Dead Viability/Cytotoxicity Assay was used to determine the ratio of dead to live cells for monolayer chondrocyte cultures compared with controls. Damage to the cartilage extracellular matrix (ECM) in en bloc cartilage samples was evaluated by analysis of DNA, glycosaminoglycan (GAG), and collagen content.
Results: Chondrocytes treated for 3 hours with a single dose of 1% lidocaine exhibited significantly more cell death (7.9%) compared with control media (2.9%; P < .001). No significant difference in cell death was observed in chondrocytes treated for 6 hours with 0.25% bupivacaine (2.7%) versus controls (2.8%; P = .856) or cells treated for 12 hours in 0.5% ropivacaine (2.9%) versus controls (2.4%; P = .084). There was no significant difference in GAG expression (P = .627) or DNA-normalized GAG expression (P = .065) between the intact cartilage treatment groups; however, the DNA-normalized GAG expression was markedly lower in cartilage cultures treated with 1% lidocaine (3.36 ± 1.15) compared with those in control media (7.61 ± 3.83).
Conclusion: The results of this in vitro study indicate that a single-dose administration of 1% lidocaine resulted in a significant decrease in chondrocyte viability when compared with control cultures.
Clinical Relevance: Single-dose injections of 1% lidocaine may be significantly chondrotoxic, and further investigation regarding in vivo chondrotoxicity appears warranted.
Background: Recent clinical and basic science investigations have revealed the chondrotoxicity of local anesthetics, especially those containing epinephrine, administered via an intra-articular pain pump. However, the exact mechanism of toxicity is unknown. This study evaluates the chondrotoxicity of low pH, epinephrine, and preservatives found in commonly used local anesthetics.
Hypothesis: The chondrotoxicity of local anesthetics containing epinephrine is due to low pH, epinephrine, or the preservative sodium metabisulfite.
Study Design: Controlled laboratory study.
Methods: Human chondrocytes were harvested and cultured in a custom bioreactor designed to simulate metabolism of medication. Pain pumps were used to infuse one of the following medications into the culture system: control media; media titrated to pH 4.5, 5.0, 5.5, 6.0, 6.5; media with 1:100000 or 1:200000 epinephrine only; media with 0.5 mg/mL of sodium metabisulfite preservative; media with 0.5 mg/mL of methylparaben preservative, 0.25% bupivacaine, 0.25% bupivacaine with epinephrine, 1% lidocaine, and 1% lidocaine with epinephrine. Cultures were perfused for 24 hours and then were stained with live/dead cell viability assay. The chondrocytes were then examined by fluorescence microscopy and counted, and the percentage of cell death was calculated.
Results: Cultures containing media titrated to pH 4.5 and 5.0 and local anesthetics containing epinephrine (pH 4.0-5.5) had high cell death rates compared with controls at all time points (P < .001), while cultures containing 1:100000 and 1:200000 epinephrine alone had no increased death rate. Also, 0.5 mg/mL sodium metabisulfite preservative had a significant effect on cell death (P < .034); however, the preservative methylparaben had no effect (P > .05). The percentage of cell death was not significant for 1% lidocaine (12.5%; P > .943) and 0.25% bupivacaine (16.5%; P > .609).
Conclusion: The marked chondrotoxicity of local anesthetics containing epinephrine appears to be a combined effect of low pH, as these medications are titrated to pH 4.0 to 5.5 for product stability, and the preservative sodium metabisulfite. Extreme caution should be exercised when using intra-articular pain pumps with local anesthetics containing epinephrine.
Clinical Relevance: Understanding the causes of chondrotoxicity using local anesthetics containing epinephrine is critical to decrease complications associated with this class of medications.
Background: Microfracture and drilling elicit a cartilage repair whose quality depends on subchondral bone repair. Alternatively activated (AA) macrophages express arginase-1, release angiogenic factors, and could be potential mediators of trabecular bone repair.
Hypothesis: Chitosan–glycerol phosphate (GP)/blood implants elicit arginase-1+ macrophages in vivo through neutrophil-dependent mechanisms and improve trabecular bone repair of drilled defects compared with drilling alone.
Study Design: Controlled laboratory study.
Methods: Bilateral trochlear cartilage defects were created in 15 rabbits, microdrilled, and treated or not with chitosan-GP/blood implant to analyze AA macrophages, CD-31+ blood vessels, bone, and cartilage repair after 1, 2, or 8 weeks. Neutrophil and macrophage chemotaxis to rabbit subcutaneous implants of autologous blood and chitosan-GP (±blood) was quantified at 1 or 7 days. In vitro, sera from human chitosan-GP/blood and whole blood clots cultured at 37°C were analyzed by proteomics and neutrophil chemotaxis assays.
Results: Chitosan-GP/blood clots and whole blood clots released a similar profile of chemotactic factors (PDGF-BB, IL-8/CXCL8, MCP-1/CCL2, and no IL-1β or IL-6), although chitosan clot sera attracted more neutrophils in vitro. Subcutaneous chitosan-GP (±blood) implants attracted more neutrophils (P < .001) and AA macrophages than whole blood clots in vivo. In repairing subchondral drill holes, chitosan-GP/blood implant attracted more AA macrophages at 1 and 2 weeks and more blood vessels at 2 weeks compared with drilled controls. Treatment elicited a more complete woven bone repair at 8 weeks than controls (P = .0011) with a more uniform, integrated collagen type II+ cartilage repair tissue.
Conclusion and Clinical Relevance: AA macrophages may play a role in the regeneration of subchondral bone, and chitosan-GP can attract and transiently accumulate these cells in the repair tissue. The resulting improved subchondral repair could be advantageous toward enhancing integration of a restored chondral surface to the subchondral bone.
