Time-dependent hyper-viscoelastic parameter identification of human articular cartilage and substitute materials.

Numerical simulations are a valuable tool to understand which processes during mechanical stimulations of hydrogels for cartilage replacement influence the behavior of chondrocytes and contribute to the success or failure of these materials as implants. Such simulations critically rely on the correct prediction of the material response through appropriate material models and corresponding parameters. In this study, we identify hyper-viscoelastic material parameters for numerical simulations in COMSOL Multiphysics® v. 5.6 for human articular cartilage and two replacement materials, the commercially available ChondroFillerliquid and oxidized alginate gelatin (ADA-GEL) hydrogels. We incorporate the realistic experimental boundary conditions into an inverse parameter identification scheme based on data from multiple loading modes simultaneously, including cyclic compression-tension and stress relaxation experiments. We provide individual parameter sets for the unconditioned and conditioned responses and discuss how viscoelastic effects are related to the materials' microstructure. ADA-GEL and ChondroFillerliquid exhibit faster stress relaxation than cartilage with lower relaxation time constants, while cartilage has the largest viscoelastic stress contribution. The elastic response predominates in ADA-GEL and ChondroFillerliquid, while the viscoelastic response predominates in cartilage. These results will help to simulate mechanical stimulations, support the development of suitable materials with distinct mechanical properties in the future and provide parameters and insight into the time-dependent material behavior of human articular cartilage.

Hyperelastic parameter identification of human articular cartilage and substitute materials.

Numerical simulations are a valuable tool in the field of tissue engineering for cartilage repair and can help to understand which mechanical properties affect the behavior of chondrocytes and contribute to the success or failure of surrogate materials as implants. However, special attention needs to be paid when identifying corresponding material parameters in order to provide reliable numerical predictions of the material's response. In this study, we identify hyperelastic material parameters for numerical simulations in COMSOL Multiphysics® v. 5.6 for human articular cartilage and two surrogate materials, commercially available ChondroFillerliquid, and oxidized alginate-gelatin (ADA-GEL) hydrogels. We consider several hyperelastic isotropic material models and provide separate parameter sets for the unconditioned and the conditioned material response, respectively, based on previously generated experimental data including both compression and tension experiments. We compare a direct parameter identification approach assuming homogeneous deformation throughout the specimen and an inverse approach, where the experiments are simulated using a finite element model with realistic boundary conditions in COMSOL Multiphysics® v. 5.6. We demonstrate that it is important to consider both compression and tension data simultaneously and to use the inverse approach to obtain reliable parameters. The one-term Ogden model best represents the unconditioned response of cartilage, while the conditioned response of cartilage and ADA-GEL is equally well represented by the two-term Ogden and five-term Mooney-Rivlin models. The five-term Mooney-Rivlin model is also most suitable to model the unconditioned response of ADA-GEL. For ChondroFillerliquid, we suggest using the five-term Mooney-Rivlin or two-term Ogden model for the unconditioned and the two-term Ogden model for the conditioned material response. These results will help to choose appropriate material models and parameters for simulations of whole joints or to advance mechanical-stimulation assisted cartilage tissue engineering in the future.

Complex mechanical behavior of human articular cartilage and hydrogels for cartilage repair.

The mechanical behavior of cartilage tissue plays a crucial role in physiological mechanotransduction processes of chondrocytes and pathological changes like osteoarthritis. Therefore, intensive research activities focus on the identification of implant substitute materials that mechanically mimic the cartilage extracellular matrix. This, however, requires a thorough understanding of the complex mechanical behavior of both native cartilage and potential substitute materials to treat cartilage lesions. Here, we perform complex multi-modal mechanical analyses of human articular cartilage and two surrogate materials, commercially available ChondroFillerliquid, and oxidized alginate-gelatin (ADA-GEL) hydrogels. We show that all materials exhibit nonlinearity and compression-tension asymmetry. However, while hyaline cartilage yields higher stresses in tension than in compression, ChondroFillerliquid and ADA-GEL exhibit the opposite trend. These characteristics can be attributed to the materials' underlying microstructure: Both cartilage and ChondroFillerliquid contain fibrillar components, but the latter constitutes a bi-phasic structure, where the 60% nonfibrillar hydrogel proportion dominates the mechanical response. Of all materials, ChondroFillerliquid shows the most pronounced viscous effects. The present study provides important insights into the microstructure-property relationship of cartilage substitute materials, with vital implications for mechanically-driven material design in cartilage engineering. In addition, we provide a data set to create mechanical simulation models in the future.

Numerical simulation of the electric field distribution in an electrical stimulation device for scaffolds settled with cartilaginous cells.

Electrical stimulation is a promising approach to enhance cell viability and differentiation. We aim to develop a stimulation device for the investigation and realization of cartilaginous cell engineering. The stimulation setup is capable of applying well-defined electric fields to several scaffolds at the same time. The setup consists of a flat plate with multiple test tubes for the scaffolds. A flexible printed circuit board containing a separate pair of electrodes for each tube is fixed at the bottom of the plate. In this context, numerical simulation using Finite Element Method (FEM) is a valuable tool to gain a better understanding of the electric field distribution in such devices. The thin insulating layer of the flexible printed circuit board allows sufficient field strength to be achieved at moderate input voltages but presents challenges for modelling. In simulations, thin layers would usually require a fine discretization with many degrees of freedom (DOF). This leads to large models, which are expensive regarding memory and computation time. Based on the 'contact impedance' boundary condition available in COMSOL Multiphysics® 5.4, an alternative approach is proposed that can model thin layers in capacitively coupled setups. The resulting electric field distribution in the new stimulation setup is presented and discussed.

[Lipid therapy in daily routine]. / Lipidtherapie im Alltag.

Patients with increased cardiovascular risk profile are frequently seen in general practice. Comprehensive management of modifiable risk factors, in particular dyslipidemia, is mandatory. Many studies in clinical practice have shown a gap between the recommendations in clinical guidelines and the actual situation. Current data on the management situation of patients with high cardiovascular risk is provided by the prospective registry LIMA. Primary care physicians in 2,387 offices throughout Germany documented 13,924 patients with coronary artery disease (CAD), diabetes mellitus or peripheral arterial disease (PAD). Treatment with simvastatin 40 mg was an inclusion criterion. Physicians documented drug utilization, laboratory values (lipids, blood glucose), blood pressure and clinical events over one year and received feedback about the target value attainment of their patients after data entry. Mean age of the patients was 65.7 years, and 61.6 % were men. CAD was reported in 70.6 %, diabetes mellitus in 58.2 % and PAD in 14.9 %. Most patients (68 %) received simvastatin as monotherapy also after the inclusion visit; 20.6 % of patients received in addition the cholesterol absorption inhibitor (ezetimibe) in the first 6 months, and 23.3 % in the second 6 months. Patients achieved the LDL-cholesterol target value in 31.8 % at entry and 50.0 % after one year. The blood pressure target < 140 /90 mmHg was reached by 65.8 % after one year. Of patients with diabetes mellitus 40.0 % reached an HbA1c value below 6.5 %. Clinical events (death, hospitalization, (cardio-) vascular events, and dialysis) were reported by 11.7 % of patients between entry and Month 6, and by 12.0 % between Month 7 and 12. In daily practice comprehensive management of risk factors in patients at high cardiovascular risk remains a challenge. For normalization of increased LDL cholesterol values addition of ezetimibe to existing statin therapy improves the chances of patients for target level attainment.

Lipid-lowering therapy and cholesterol levels following acute myocardial infarction: a German study of 5361 patients.

BACKGROUND: Current studies on secondary prevention of cardiovascular events (CARE, LIPID, 4S) illustrate the necessity of an effective lipid-lowering therapy. An important part of secondary prevention is the prompt measurement of lipids following an infarct, to be able to start therapy as quickly as possible. AIMS: This study should show the general situation in the prescription of lipid-lowering drugs in patients with acute myocardial infarction (MI) and if there are gender differences in therapy and in the lipid parameters. The second aim was to determine the therapeutical conclusions for secondary prevention made in-hospital in patients with heart attacks. METHODS: Post-infarct lipid parameters (total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) were examined in 5361 patients within 24 hours following an acute MI. Lipid parameters from 576 patients were measured again after 1 week. RESULTS: 80.1% of men under examination and 81.9% of the women had suffered from their first MI. Only 9% of all patients were already under lipid-lowering therapy before the MI. After the MI TC and LDL-C levels decreased significantly in a time-dependent manner. Around 50% of patients received lipid-lowering drug, or the recommendation of one, during their hospital stay. CONCLUSION: The range of TC values of the patients examined was comparable to those in the CARE and the 4S secondary prevention studies. It can therefore be assumed that the results of these studies are also applicable to Germany. Nevertheless, according to existing data, therapy with lipid-lowering drugs is currently unsatisfactory, even in secondary prevention.

[Current prescription practice of CSE inhibitors at clinic discharge after acute myocardial infarct]. / Aktuelle Verordnungspraxis von CSE-Hemmern bei Entlassung aus der Klinik nach akutem Myokardinfarkt.

We investigated the use of statins in clinical practice in patients with acute myocardial infarction in Germany in 17,732 consecutively included patients of the registries MIR-1 and MITRA-1. A clinical follow-up has been performed in the MITRA-1 study after a mean period of 18 months. In total 30% of all patients with acute myocardial infarction received statins at discharge. From 1994 to 1998 the use of statins increased from 6% to 44%; however in 1998 still less than half of the patients with acute myocardial infarction received statins at discharge. In a logistic regression model, concomittant diseases as renal failure (OR 0.7), heart failure (OR 0.7) and diabetes mellitus (OR 0.9) were associated with a lower use of statins. Age > 70 years (OR 0.5) was also associated with a lower use of statins at hospital discharge. Patients with statins at discharge had a lower long-term mortality of 5.8% versus 12.9% in patients without statins. After adjustment to age and comorbidity, use of statins at discharge was associated with a borderline significant reduction of long-term mortality (multivariate OR 0.7, 95% CI 0.4-1.0). In a subgroup analysis of therapeutic benefit, measured by the "number needed to treat" (NNT), the number of patients to treat with statins to save one life, patients with cardiovascular risk factors, as heart failure (NNT 7.5), diabetes mellitus (NNT 7.8) and age > 70 years (NNT 13.8) had a larger therapeutic benefit as patients without these risk factors (NNT 345). However, these high-risk patients received less often statins than patients without risk factors (use of statins 11.8% versus 19.8%).

[Therapy with CSE inhibitors--more than lipid lowering?]. / Therapie mit CSE-Hemmern--mehr als Lipidsenkung?

An elevated plasma cholesterol concentration is an established risk factor for coronary heart disease. Dietary and drug interventions with fibrate, nicotinic acid and colestyramine have resulted in a decreased rate of major coronary events but failed to decrease mortality. Studies using the more potent lipid lowering statins have shown remarkable results in primary (WOSCOPS, AFCAPS, TexCAPS) and secondary prevention (4S, CARE, LIPID). The use of these drugs reduced the risk for coronary events as well as the need for interventions. Furthermore, improvement of angina has been shown in several studies. In high-risk patients coronary heart disease associated mortality and overall mortality was reduced. Lowering of cholesterol was shown to be effective in women, older people and diabetics. Lipid lowering improves prognosis after heart transplant and could be an alternative to PTCA. Furthermore it was also shown that cholesterol lowering reduces the incidence of stroke. New mechanisms are discussed to explain the rapid onset of clinical improvement. Among these are: influences on inflammatory processes in the plaque, on vascular smooth muscle activity, on coagulation and on endothelial dysfunction.

Drug therapy of severe hypercholesterolemia.

Lowering of plasma cholesterol and particularly of LDL cholesterol has been shown to be an effective way of primary and secondary prophylaxis of coronary heart disease. A broad range of drugs is available (bile acid binding resins, HMG CoA reductase inhibitors, fibrates, nicotinic acid, probucol, beta-sitosterol) for therapy. The choice of the drug is based on the efficacy, possible side effects and proven effects on coronary heart disease.

Passage of a large bilirubin stone through a narrow papillotomy.

Large stones in the bile are generally considered to be a contraindication for endoscopic papillotomy (EPT). In the case described a large biliary stone passed spontaneously into the lumen of the gut after EPT. It is speculated that pure pigment stones are less "rigid" than cholesterol stones and are therefore able to pass through narrower channels than cholesterol stones.

Influence of portocaval anastomosis on lipid parameters in patients with alcoholic cirrhosis.

The effect of portocaval shunt operation on lipid metabolism was investigated in 10 patients with alcoholic cirrhosis. Portocaval shunt operation resulted in a significant decrease of concentration of total serum cholesterol, total serum triglycerides, LDL cholesterol, VLDL cholesterol, VLDL triglycerides, and LCAT activity. The concentrations of free cholesterol, esterified cholesterol, phospholipids, LDL triglycerides, HDL cholesterol, and HDL triglycerides were unaffected.

Acute dietary effects on plasma lipids, lipoproteins and lipolytic enzymes in healthy normal males.

Diurnal plasma lipids and lipoproteins were studied in twelve healthy young males on corn oil and palm oil diets, respectively. The major triglyceridy. Lecithin-cholesterol acyl transferase, lipoprotein lipase and hepatic triglyceride lipase were also measured. diurnal changes of triglycerides and cholesterol were confined to lipoproteins of d less than 1.006 kg/l. There was a diurnal rise of lecithin-cholesterol acyl transferase activity with corn oil but not with palm oil. Fasting and postprandial postheparin lipoprotein lipase and hepatic triglyceride lipase were similar but there was a significant correlation of postprandial hepatic lipase with postprandial plasma triglycerides on palm oil. Marked diurnal changes of triglyceride fatty acids were observed not only in 'very low density lipoprotein' but also in high-density lipoprotein amounting to approximately one third of total high density lipoprotein triglyceride fatty acids.

Renal excretion of contrast medium after endoscopic retrograde investigations.

Endoscopic retrograde investigations are often performed as diagnostic procedures. The investigation of urine after such procedures in 21 patients has shown that appreciable amounts of contrast medium can be excreted renally. No such excretion could be shown when the contrast medium was injected into the gut lumen. The fact that contrast medium can be absorbed into the liver the pancreas during endoscopic retrograde procedures should influence the decision to perform these studies in patients with known allergies.

Secondary hypertriglyceridaemia in patients with parenchymal liver disease.

Hypertriglyceridaemia occurring in patients with liver disease has been studied by measuring hepatic triglyceride lipase (H-TGL) and plasma lipoprotein lipase (LPL) by selective precipitation of H-TGL with specific antibodies. Lipid analysis, determination of lecithin-cholesterol-acyltransferase (LCAT) activity, and liver function tests were performed in parallel in fifty patients with acute hepatitis, twenty patients with chronic active or persistent hepatitis and fifty with cirrhosis of the liver. Total post-heparin lipolytic activity (PHLA) decreased with the severity of liver dysfunction. This decrease was due to low H-TGL and only to some degree to low LPL activity. With improvement over several weeks of hospitalization, hypertriglyceridaemia disappeared with a concomitant increase of H-TGL and LPL. It is concluded that impaired triglyceride metabolism in liver disease is at least partly caused by diminished plasma hepatic TGL activity.

Demonstration of a liver abscess by ERC.

In a patient with septic fever and elevated alkaline phosphatase an ERC was conducted to explore the biliary system. Contrast media could be demonstrated within the hepatic parenchyma, establishing the diagnosis of a liver abscess in communication with the intrahepatic biliary system.