Hubert T. Kim

Comparison of ropivacaine and bupivacaine toxicity in human articular chondrocytes.

BACKGROUND It has been shown that bupivacaine, the most commonly used local anesthetic for postoperative intra-articular use, is cytotoxic to bovine articular chondrocytes in vitro. Ropivacaine is as effective as bupivacaine for intra-articular analgesia and has less systemic toxicity. We compared the in vitro viability of human articular chondrocytes after exposure to bupivacaine, ropivacaine, and saline solution control. METHODS Macroscopically normal human articular cartilage was harvested from the femoral head or tibial plateau of five patients. Full-thickness cartilage explants and cultured chondrocytes isolated from these patients were treated with 0.9% normal saline solution, 0.5% ropivacaine, or 0.5% bupivacaine for thirty minutes. Twenty-four hours after treatment, chondrocyte viability was measured with use of the LIVE/DEAD Viability/Cytotoxicity Kit for cartilage explants and with use of the CellTiter-Glo Luminescent Cell Viability Assay for cultured chondrocytes. RESULTS Chondrocyte viability in cartilage explants was significantly greater after treatment with ropivacaine as compared with bupivacaine (94.4% +/- 9.0% compared with 78% +/- 12.6%; p = 0.0004). There was no difference in viability after treatment with ropivacaine as compared with saline solution (94.4% +/- 9.0% compared with 95.8% +/- 5.7%; p = 0.6). The viability of cultured chondrocytes was significantly greater after treatment with ropivacaine as compared with bupivacaine (63.9% +/- 19% as compared with 37.4% +/- 12% of the value in the saline solution group; p < 0.0001). CONCLUSIONS In vitro, 0.5% ropivacaine is significantly less toxic than 0.5% bupivacaine in both intact human articular cartilage and chondrocyte culture.

Effects of Local Anesthetics on Articular Cartilage

Background: Recent basic science studies have demonstrated local anesthetic chondrotoxicity in vivo and in vitro in both human and animal cartilage. Clinically, chondrolysis associated with the use of intra-articular local anesthetic pain pumps has been described by several groups. This has raised concern regarding the clinical use of intra-articular local anesthetics. Methods: The authors undertook a review of the current orthopaedic literature on local anesthetic chondrotoxicity and its potential relationship to clinical chondrolysis. Results: Local anesthetics such as bupivacaine, lidocaine, and ropivacaine are chondotroxic to human articular cartilage in vitro, although ropivacaine is less so. The evidence suggests that there is a greater risk for chondrolysis with a longer exposure to a higher concentration of local anesthetic, such as with a pain pump, than with a single injection. However, late cellular and metabolic changes are seen after even a single injection of bupivacaine in animal models, and the loss of an intact cartilage matrix also leads to more extensive chondrocyte death. Some studies suggest that additives and the pH of the local anesthetic solution may also play a role in chondrotoxicity. Conclusion: Intra-articular local anesthetics should be used with caution, especially continuous infusions of bupivacaine and lidocaine at high concentrations in joints with compromised cartilage. The consequences of a single intra-articular injection of local anesthetic remains unclear and requires further investigation. Clinical Relevance: Intra-articular use of local anesthetics may have lasting detrimental effects on human articular cartilage and chondrocytes, although the clinical relationship between local anesthetic exposure and chondrolysis requires further study.

A rat model of massive rotator cuff tears

Rotator cuff tears (RCTs) are the most common tendon injury seen in orthopedic patients. Massive RCT does not heal spontaneously and results in poor clinical outcomes. Muscle atrophy and fatty infiltration in rotator cuff muscles are major complications of chronic massive RCT and are thought to be the key factors responsible for the failure of attempted massive RCT repair. However, the pathophysiology of rotator cuff muscle atrophy and fat infiltration remains largely unknown, and no small animal model has been shown to reproduce the histologic and molecular changes seen in massive RCT. In this article, we report a novel rat massive RCT model, in which significant and consistent muscle atrophy and fat infiltration were observed in the rotator cuff muscles after rotator cuff tendon transection and denervation. The supraspinatus and infraspinatus muscle lost 25.4% and 28.9% of their wet weight 2 weeks after complete tendon transection, respectively. Six weeks after surgery, the average wet weight of supraspinatus and infraspinatus muscles decreased 13.2% and 28.3%, respectively. Significant fat infiltration was only observed in infraspinatus 6 weeks after tendon transection.

Structured three-dimensional co-culture of mesenchymal stem cells with chondrocytes promotes chondrogenic differentiation without hypertrophy

OBJECTIVE This study investigated a novel approach to induce chondrogenic differentiation of human mesenchymal stem cells (hMSC). We hypothesized that a structured three-dimensional co-culture using hMSC and chondrocytes would provide chondroinductive cues to hMSC without inducing hypertrophy. METHOD In an effort to promote optimal chondrogenic differentiation of hMSC, we created bilaminar cell pellets (BCPs), which consist of a spherical population of hMSC encased within a layer of juvenile chondrocytes (JC). In addition to histologic analyses, we examined proteoglycan content and expression of chondrogenic and hypertrophic genes in BCPs, JC pellets, and hMSC pellets grown in the presence or absence of transforming growth factor-β (TGFβ) following 21 days of culture in either growth or chondrogenic media. RESULTS In either growth or chondrogenic media, we observed that BCPs and JC pellets produced more proteoglycan than hMSC pellets treated with TGFβ. BCPs and JC pellets also exhibited higher expression of the chondrogenic genes Sox9, aggrecan, and collagen 2A1, and lower expression of the hypertrophic genes matrix metalloproteinase-13, Runx2, collagen 1A1, and collagen 10A1 than hMSC pellets. Histologic analyses suggest that JC promote chondrogenic differentiation of cells in BCPs without hypertrophy. Furthermore, when cultured in hypoxic and inflammatory conditions intended to mimic the injured joint microenvironment, BCPs produced significantly more proteoglycan than either JC pellets or hMSC pellets. CONCLUSION The BCP co-culture promotes a chondrogenic phenotype without hypertrophy and, relative to pellet cultures of hMSCs or JCs alone, is more resistant to the adverse conditions anticipated at the site of articular cartilage repair.

Chondrocyte apoptosis induced by collagen degradation: Inhibition by caspase inhibitors and IGF-1

The main objective of this study was to test the effectiveness of candidate apoptosis inhibitors in limiting chondrocyte apoptosis induced by collagen degradation. Primary human chondrocytes were isolated from normal articular cartilage and grown in monolayer culture. Collagenase was added to the cells in the presence and absence of caspase inhibitors and insulin like growth factor (IGF)‐1. The amount of chondrocyte apoptosis was measured using an enzyme linked immunosorbent assay for nucleosomes, a specific and quantitative measure of apoptosis. Chondrocyte apoptosis was induced by collagenase treatment in both a time and dose dependent manner. The non‐selective caspase inhibitor Z‐VAD, the caspase‐3 selective inhibitor Z‐DEVD, and the growth factor insulin like growth factor (IGF)‐1 inhibited chondrocyte apoptosis induced by collagenase treatment. The caspase‐1 selective inhibitor Z‐YVAD also blocked chondrocyte apoptosis under these conditions, in contrast to previous studies where caspase‐1 inhibition failed to block apoptosis induced by agents such as the topoisomerase inhibitor camptothecin. These data demonstrate that the response of chondrocytes to caspase inhibition may be dependent upon the specific stimulus that initiates apoptosis. Furthermore, these findings suggest that multiple pathways involving both the initiation and execution of programmed cell death are potential targets for chondrocyte apoptosis inhibition therapy.

Early failure due to osteolysis associated with contemporary highly cross-linked ultra-high molecular weight polyethylene. A case report.

Cross-linking changes the wear and mechanical behavior of ultra-high molecular weight polyethylene. Contemporary highly cross-linked ultra-high molecular weight polyethylene has demonstrated markedly improved wear in vitro and a reduction in static and fatigue strength compared with conventional ultra-high molecular weight polyethylene1-7. Studies employing hip simulators have shown a reduction in the volume of wear debris generated with cross-linked polyethylene in comparison with that generated with conventional polyethylene8. However, the average size of wear particles also appeared to be reduced, which means that the actual number of generated particles may not be decreased8. The osteolytic response to particulate debris is variable and may depend more on a number of factors, including the number and the size of particles, than on the total volume of debris generated9,10. The long-term clinical results of the use of currently available contemporary highly cross-linked ultra-high molecular weight polyethylene components in total hip arthroplasty are not yet known. The following case demonstrates that early symptomatic osteolysis associated with impingement can occur with the use of contemporary highly cross-linked ultra-high molecular weight polyethylene components in total hip arthroplasty. Our patient was informed that data concerning the case would be submitted for publication. Asixty-year-old woman underwent a right hybrid total hip arthroplasty, without complications, for the treatment of osteoarthritis in July of 2000. The components that were implanted included a Trilogy (Zimmer, Warsaw, Indiana) 58-mm acetabular shell, a Longevity (Zimmer) 58/28-mm polyethylene acetabular cup with a 10° offset lip, a Perfecta PDA (Wright Medical, Arlington, Tennessee) 13.5-cm femoral stem, a 28-mm cobalt-chromium femoral head (Wright Medical) with a +10.5-cm neck length, and a 13-mm distal spacer (Wright Medical). The femoral component was a forged steel implant with a surface-grit-blasted stem. The hospital course was uncomplicated, and the …

Muscle degeneration in rotator cuff tears

Rotator cuff tears are among the most common injuries seen by orthopedic surgeons. Although small- and medium-sized tears do well after arthroscopic and open repair, large and massive tears have been shown to develop marked muscle atrophy and fatty infiltration within the rotator cuff muscles. These pathologic changes have been found to be independent predictors of failed surgical repair with poor functional outcomes. To understand the pathophysiology of rotator cuff disease, we must first develop an understanding of the changes that occur within the cuff muscles themselves. The purpose of this review is to summarize the molecular pathways behind muscular degeneration and emphasize new findings related to the clinical relevance of muscle atrophy and fatty infiltration seen with rotator cuff tears. Understanding these molecular pathways will help guide further research and treatment options that can aim to alter expression of these pathways and improve outcomes after surgical repair of massive rotator cuff tears.

The Use of Scaffolds in the Management of Articular Cartilage Injury

Managing articular cartilage injury continues to be a difficult challenge for the clinician. Although the short- and intermediate-term results of autologous chondrocyte implantation appear to be favorable, resources are being directed toward research to improve the technology. One promising area of investigation is the combination of cultured chondrocytes with scaffolds. Clinicians desire techniques that may be implanted easily, reduce surgical morbidity, do not require harvesting of other tissues, exhibit enhanced cell proliferation and maturation, have easier phenotype maintenance, and allow for efficient and complete integration with surrounding articular cartilage. The characteristics that make scaffolds optimal for clinical use are that they be biocompatible, biodegradable, permeable, reproducible, mechanically stable, noncytotoxic, and capable of serving as a temporary support for the cells while allowing for eventual replacement by matrix components synthesized by the implanted cells. Clinical experience is growing with three scaffold-based cartilage repair techniques, each using a different type of scaffold material: matrix-induced autologous chondrocyte implantation, a hyaluronic acid-based scaffold, and a composite polylactic/polyglycolic acid polymer fleece. Clinical results are encouraging. Future directions in scaffold-based cartilage repair include bioactive and spatially oriented scaffolds.

Complications of Morbid Obesity in Total Joint Arthroplasty: Risk Stratification Based on BMI

This study stratifies complication risk in primary total joint arthroplasty (TJA) based on body mass index (BMI). Demographics, co-morbidities, perioperative variables, and complications were reviewed for 22,808 patients. Chi-squared, one-way ANOVA, univariate and multivariable regression analysis were performed. Increasing BMI led to an increase (P<0.05) in combined complications, acute kidney injury (AKI), cardiac arrest (CA), reintubation, reoperation, and superficial infection (SI). Univariate analysis for BMI>40 revealed an increase in combined complications (15.21-vs-17.40%), AKI (1.93-vs-3.87%), CA (0.22-vs-0.57%), reintubation (0.47-vs-0.95%), reoperation (2.36-vs-3.37%), and SI (0.82-vs-1.65%). Multivariable regression showed BMI>40 as an independent predictor for combined complications (OR=1.18), AKI (OR=1.79), CA (OR=3.94), reintubation (OR=2.56), reoperation (OR=1.44), and SI (OR=2.11). Morbid obesity confers increased risk for complications in TJA.

A Mouse Model of Massive Rotator Cuff Tears

BACKGROUND Rotator cuff tears are the most common tendon injury seen in orthopaedic patients. Muscle atrophy and fatty infiltration in rotator cuff muscles are considered among the key factors responsible for the failure of attempted repair of a massive rotator cuff tear. However, the pathophysiology of rotator cuff muscle atrophy and fatty infiltration remains largely unknown, partly because of the lack of appropriate small animal models. The goal of this study was to develop a mouse model of muscle atrophy and fatty infiltration after a rotator cuff tear. We also sought to study the role of denervation on muscle atrophy and fatty infiltration after a rotator cuff tear. METHODS Adult wild-type FVB/N mice were randomly divided into three groups. Mice in different groups received unilateral complete supraspinatus and infraspinatus tendon transection, suprascapular nerve transection, or both procedures. Sham surgery was performed on the contralateral shoulder to serve as a control. Mice were killed twelve weeks after surgery. Histological analysis and high-resolution magnetic resonance imaging were used to evaluate muscle atrophy and fat infiltration after a rotator cuff tear. RESULTS Significant and consistent muscle atrophy and fatty infiltration were observed in the rotator cuff muscles after rotator cuff tendon transection. We further found that denervation significantly increases the amount of muscle atrophy and fatty infiltration after a rotator cuff tear. CONCLUSIONS We successfully developed a novel mouse model of a massive rotator cuff tear, which simulates major pathological changes, including muscle atrophy and fatty infiltration after massive rotator cuff tears seen in patients.