Extracellular matrix changes in knee joint cartilage following bone-active drug treatment

Meniscal injury is more likely to cause a permanent alteration of the biomechanical and biological environment of the knee joint, mainly due to the morphological mismatch and substantial loss of meniscal tissues. Herein, to overcome this challenge, we developed an improved bioink with enhanced printability, while maintaining the biocompatibility of major cellular component of the meniscus, namely fibrochondrocytes. Firstly, cellulose nanofiber (CNF) was mixed with gelatin-alginate thermal-responsive bioinks to improve the printability. Afterward, individual-specific meniscal prototypes based on the 3D reconstruction of MRI data were bioprinted using our bioink. The rheological and printability properties of the bioinks were characterized to select proper bioink content and bioprinting parameters. And then, a series of biological characterizations of the bioprinted samples, such as cell viability, metabolic activity, and extracellular matrix accumulation, were carried out in vitro. The results indicated that superior rheological performance and printability of CNF-modified bioink were achieved, ensuring high-precision bioprinting of specific-designed meniscal prototype when compared with the non-CNF-containing counterparts. Meanwhile, biological tests indicated that fibrochondrocytes encapsulated within the CNF-modified bioink maintained long-term cellular viability as well as acceptable extracellular matrix accumulation. This study demonstrates that the CNF-modified bioink is in favor of the printing fidelity of specific meniscus by improved rheological properties, minimizing the mismatch between artificial meniscal implants and native knee joint tissues, thereby permitting the evolution of clinical therapeutic methods of meniscal reconstruction.

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Impact of daily exercise dose on knee joint cartilage thickness in healthy animals – a meta-analysis of published randomized control trials

Osteoarthritis and Cartilage ◽

10.1016/j.joca.2016.01.731 ◽

2016 ◽

Vol 24 ◽

pp. S404

Author(s):

A. Bricca ◽

C.B. Juhl ◽

M. Steultjens ◽

E.M. Roos

Keyword(s):

Knee Joint ◽

Meta Analysis ◽

Cartilage Thickness ◽

Randomized Control Trials ◽

Joint Cartilage ◽

Daily Exercise ◽

Randomized Control ◽

Exercise Dose

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Chondrotoxicity and Toxicokinetics of Sparfloxacin in Juvenile Rats

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.6.1470 ◽

1998 ◽

Vol 42 (6) ◽

pp. 1470-1475 ◽

Cited By ~ 18

Author(s):

Ralf Stahlmann ◽

Uta Zippel ◽

Christian Förster ◽

Rudolf Schwabe ◽

Mehdi Shakibaei ◽

...

Keyword(s):

Body Weight ◽

Oral Dose ◽

Knee Joint ◽

Species Differences ◽

Joint Cartilage ◽

Juvenile Rats ◽

Cartilage Lesions ◽

Old Rats ◽

Immunohistochemical Studies ◽

Oral Doses

ABSTRACT Sparfloxacin is a fluoroquinolone with improved antibacterial activity against gram-positive pathogens. Like other quinolones, use of this drug is contraindicated in children and adolescents because of its potential chondrotoxicity in juveniles. We performed histological and immunohistochemical studies on the knee joint cartilage in 5-week-old rats after treatment with 600 or 1,800 mg of sparfloxacin/kg of body weight. Treatment with single or multiple oral doses of 600 mg of sparfloxacin/kg was not sufficient to induce joint cartilage lesions. However, five of eight rats treated with a single oral dose of 1,800 mg of sparfloxacin/kg of body weight showed typical cartilage lesions in the femoral part of the knee joint. The concentrations of the drug in plasma measured 0.25, 0.75, 1.5, 3, 6, 12, and 24 h after the administration of an oral dose of 600 mg of sparfloxacin/kg were 6.3 ± 1.8, 9.2 ± 1.7, 9.6 ± 2.7, 13.0 ± 1.8, 12.3 ± 1.6, 3.4 ± 0.4, and 0.30 ± 0.20 mg/liter, respectively (mean ± standard deviation [SD];n = 5 to 6 per group). The concentrations in plasma measured 0.75, 1.5, 3, 6, 24, and 48 h after the administration of an oral dose of 1,800 mg of sparfloxacin/kg were 10.9 ± 1.5, 15.9 ± 1.6, 19.1 ± 1.7, 14.9 ± 3.1, 4.1 ± 0.6, and 0.46 ± 0.37 mg/liter, respectively (mean ± SD;n = 3 to 4 per group). The concentrations of sparfloxacin in joint cartilage were significantly higher at all time points studied (114.8 ± 80, 99.4 ± 31.5, 84.9 ± 16.8, 44.4 ± 13.9, and 14.2 ± 4.8 mg of sparfloxacin/kg at 1.5, 3, 6, 24, and 48 h after the administration of 1,800 mg/kg, respectively). The range of concentrations in bone were similar to the range of concentrations in cartilage (peak, 115 ± 12 mg/kg after 3 h). Our data indicate that chondrotoxic doses of sparfloxacin in juvenile rats are approximately 300 times higher than the doses of sparfloxacin used therapeutically (1,800 versus approximately 6 mg/kg of body weight), but due to species differences in kinetics, concentrations in plasma differ by a factor of only approximately 15. More data on quinolone concentrations in cartilage from animals and humans could provide a better basis for a reasonable risk assessment.

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STUDY ON MECHANICAL PROPERTIES OF TOTAL KNEE ARTICULAR CARTILAGE UNDER DIFFERENT LOADING RATES

Journal of Mechanics in Medicine and Biology ◽

10.1142/s0219519419500167 ◽

2019 ◽

Vol 19 (04) ◽

pp. 1950016

Author(s):

SHILEI WANG ◽

LILAN GAO ◽

CHUNQIU ZHANG ◽

YANG SONG ◽

XIZHENG ZHANG ◽

...

Keyword(s):

Mechanical Properties ◽

Knee Joint ◽

Contact Pressure ◽

Contact Area ◽

Weight Bearing ◽

Joint Cartilage ◽

Main Bearing ◽

Loading Rates ◽

Intact Cartilage ◽

Peak Contact Pressure

Knee joint is the main weight bearing tissue of human body, also it is one of the prone parts of the clinical disease. Under different sports conditions, knee joint was loaded at different forms. In this study, the changes of average contact pressure, peak contact pressure, contact area and pressure-sharing regions were researched using the intact and defect pig knee joints under different loading rates and loads, including fast rates and large loads. These data were measured and recorded by usage of the sensor plate that placed between the unilateral meniscus and the femur cartilage during loading process. As for the intact cartilage samples, the average contact pressure and peak contact pressure of the femur cartilage increase with the loading rate, while the contact area is contrast to it. As for defect cartilage samples, it not only emerged stress concentration on the edge of the defect and pressure distribution in joint cavity was different with intact cartilage samples, but also the main bearing region was transferred from the femur cartilage-meniscus contact area to the femur cartilage-tibial cartilage contact area at different loading forms. In different loading stages, the pressure-sharing regions between the cartilage and the meniscus also changes. Different loading rates, different loads and defects will change the mechanical states of the knee joint. In loading forms, the mechanical condition may cause or aggravate damnification of the knee joint cartilage. Therefore, this study is beneficial for promoting and perfecting the research of mechanical properties of knee joint cartilage and provides a theoretical basis for the prevention and treatment of knee cartilage injury.

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P14.30 Treatment outcomes of newly-diagnosed glioblastoma multiforme (GBM) by O6-methylguanine DNA methyltransferase promoter (MGMT) status: a multi-country study

Neuro-Oncology ◽

10.1093/neuonc/noz126.265 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii73-iii73

Author(s):

A Z Fu ◽

J P Hall ◽

A Bailey ◽

J Kemp ◽

G J Thompson ◽

...

Keyword(s):

Life Expectancy ◽

Drug Treatment ◽

Treatment Outcomes ◽

Dna Methyltransferase ◽

Active Drug ◽

Data Availability ◽

Patient Treatment ◽

Newly Diagnosed ◽

Cross Sectional Survey ◽

Cross Sectional

Abstract INTRODUCTION This study evaluated the relationship of MGMT status with first-line (1L) treatment outcomes of patients with newly-diagnosed GBM in France, Germany, Italy, Spain, the UK (EU5), and Canada. MATERIALS AND METHODS Medical oncologists and neuro-oncologists across EU5 and Canada completed a point in time, cross-sectional survey for the next 8 GBM patients seen between May and July 2016 within EU5 and Canada. All results apart from time to progression (TTP) were presented for patients receiving 1L active drug treatment. TTP was calculated from initiation of 1L treatment to initiation of second-line treatment. Results presented are statistically significant (p<0.05) unless otherwise specified. Bases vary depending on data availability. RESULTS A total of 241 physicians reported on 1747 patients with GBM. 875 were receiving 1L active drug treatment at time of survey. Mean age was 59.7 years (median=61) and 34.6% were women. Mean life expectancy was 14.9 months (median=12) at diagnosis and mean TTP was 8.5 months (median=7.3). Surgery was performed in 62% of patients (n=546) prior to 1L drug treatment; 38% of patients (n=329) had no surgery. Patients with surgery had a higher life expectancy at diagnosis vs patients with no surgery prior to 1L (mean=16.4 vs 12.2 months; median=15.0 vs 12.0). Patients who received corticosteroids (n=524) vs no corticosteroids during radiotherapy (n=64) had a shorter life expectancy at diagnosis (mean=15.0 vs 16.8 months, p=0.07; median=12.5 vs 13.9) and were more likely to have 8 or more inpatient days due to GBM (21% vs 8%, p=0.07) in the last 3 months prior to the survey. 62% of patients (n=541) had an MGMT-status recorded (tested: methylated or unmethylated), and 38% (n=334) were untested/ awaiting results (untested) at 1L. MGMT-tested patients had better life expectancy at diagnosis (mean=16.1 vs 12.9 months; median=15.0 vs 12.0) and longer TTP (mean=8.9 vs 7.8 months; median=7.8 vs 6.4) than untested patients. Among MGMT-tested patients, 58% were methylated and 42% were unmethylated. Methylated patients had similar life expectancy at diagnosis (mean=15.9 vs 16.3 months, p=0.85; median=15.0 vs 15.0) and TTP (mean=9.0 vs 8.8 months, p=0.42; median=8.0 vs 7.5) as unmethylated patients. CONCLUSIONS This analysis provides valuable insights into the 1L treatment outcomes of GBM patients in EU5 and Canada. Patients who did not undergo surgery had worse treatment outcomes. Steroid use appears to be associated with worse outcomes and higher healthcare resource utilization. Patient treatment outcomes varied depending on whether they are MGMT tested.

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