Nebojsa Zdravkovic

ARTreat project: Three-dimensional numerical simulation of plaque formation and development in the arteries

Atherosclerosis is a progressive disease characterized by the accumulation of lipids and fibrous elements in arteries. It is characterized by dysfunction of endothelium and vasculitis, and accumulation of lipid, cholesterol, and cell elements inside blood vessel wall. In this study, a continuum-based approach for plaque formation and development in 3-D is presented. The blood flow is simulated by the 3-D Navier-Stokes equations, together with the continuity equation while low-density lipoprotein (LDL) transport in lumen of the vessel is coupled with Kedem-Katchalsky equations. The inflammatory process was solved using three additional reaction-diffusion partial differential equations. Transport of labeled LDL was fitted with our experiment on the rabbit animal model. Matching with histological data for LDL localization was achieved. Also, 3-D model of the straight artery with initial mild constriction of 30% plaque for formation and development is presented.

Cytotoxic Effects of Glass Ionomer Cements on Human Dental Pulp Stem Cells Correlate with Fluoride Release

OBJECTIVES Glass ionomer cements (GICs) are commonly used as restorative materials. Responses to GICs differ among cell types and it is therefore of importance to thoroughly investigate the influence of these restorative materials on pulp stem cells that are potential source for dental tissue regeneration. Eight biomaterials were tested: Fuji I, Fuji II, Fuji VIII, Fuji IX, Fuji Plus, Fuji Triage, Vitrebond and Composit. We compared their cytotoxic activity on human dental pulp stem cells (DPSC) and correlated this activity with the content of Fluoride, Aluminium and Strontium ions in their eluates. METHODS Elution samples of biomaterials were prepared in sterile tissue culture medium and the medium was tested for toxicity by an assay of cell survival/proliferation (MTT test) and apoptosis (Annexin V FITC Detection Kit). Concentrations of Fluoride, Aluminium and Strontium ions were tested by appropriate methods in the same eluates. RESULTS Cell survival ranged between 79.62% (Fuji Triage) to 1.5% (Fuji Plus) and most dead DPSCs were in the stage of late apoptosis. Fluoride release correlated with cytotoxicity of GICs, while Aluminium and Strontium ions, present in significant amount in eluates of tested GICs did not. SIGNIFICANCE Fuji Plus, Vitrebond and Fuji VIII, which released fluoride in higher quantities than other GICs, were highly toxic to human DPSCs. Opposite, low levels of released fluoride correlated to low cytotoxic effect of Composit, Fuji I and Fuji Triage.

Impact of aortic repair based on flow field computer simulation within the thoracic aorta

Purpose of this computational study is to examine the hemodynamic parameters of velocity fields and shear stress in the thoracic aorta with and without aneurysm, based on an individual patient case and virtual surgical intervention. These two cases, case I (with aneurysm) and II (without aneurysm), are analyzed by computational fluid dynamics. The 3D Navier-Stokes equations and the continuity equation are solved with an unsteady stabilized finite element method. The vascular geometries are reconstructed based on computed tomography angiography images to generate a patient-specific 3D finite element mesh. The input data for the flow waveforms are derived from MR phase contrast flow measurements of a patient before surgical intervention. The computed results show velocity profiles skewed towards the inner aortic wall for both cases in the ascending aorta and in the aortic arch, while in the descending aorta these velocity profiles are skewed towards the outer aortic wall. Computed streamlines indicate that flow separation occurs at the proximal edge of the aneurysm, i.e. computed flow enters the aneurysm in the distal region, and that there is essentially a single, slowly rotating, vortex within the aneurysm during most of the systole. In summary, after virtual surgical intervention in case II higher shear stress distribution along the descending aorta could be found, which may produce more healthy reactions in the endothelium and benefit of vascular reconstruction of an aortic aneurysm at this particular location.

Transient finite element modeling of functional electrical stimulation.

Transcutaneous functional electrical stimulation is commonly used for strengthening muscle. However, transient effects during stimulation are not yet well explored. The effect of an amplitude change of the stimulation can be described by static model, but there is no differency for different pulse duration. The aim of this study is to present the finite element (FE) model of a transient electrical stimulation on the forearm. Discrete FE equations were derived by using a standard Galerkin procedure. Different tissue conductive and dielectric properties are fitted using least square method and trial and error analysis from experimental measurement. This study showed that FE modeling of electrical stimulation can give the spatial-temporal distribution of applied current in the forearm. Three different cases were modeled with the same geometry but with different input of the current pulse, in order to fit the tissue properties by using transient FE analysis. All three cases were compared with experimental measurements of intramuscular voltage on one volunteer.

Potential dual immunomodulatory role of VEGF in ulcerative colitis and colorectal carcinoma.

Objective. Progression from ulcerative colitis (UC) toward colorectal carcinoma (CRC) is multistep process that includes gene alterations of tumor suppressor genes, such as p53 and p16. The aim of this study was to investigate the expression patterns of p16, p53 and VEGF in affected tissue and serum levels of cytokines TNF-α, IFN-γ, IL-4, IL-6, IL-10 and IL-17 in patients with UC and CRC, respectively. Matherials and methods. Serum levels of cytokine in patients with UC (n=24) and CRC (n=75) and in a healthy group (n=37) were analyzed by ELISA. Endoscopic biopsies specimens of UC and CRC were studied by immunohistochemical staining for p16, p53 and VEGF. Results. Patients with UC with presence of extraintestinal manifestations, complications, and positive staining of p16, p53 and VEGF respectively had higher serum levels of pro-inflammatory cytokines. Higher percentage of CRC patients had positive staining of p16, p53 and VEGF. CRC patients with positive staining of VEGF had decreased systemic values of pro-inflammatory IFN-γ and increased values of immunosuppressive IL-10. Conclusions. Relatively low IL-10 in patients with severe UC is insufficient to compensate IL-6 secretion and subsequently enhanced type 1/17 immune response. In UC patients, p16 and p53 induce enhanced VEGF expression and subsequent production of pro-inflammatory TNF-α and IL-6. In CRC patients VEGF seems to have immunosuppressive role. It appears that tumor suppressor gene-VEGF axis have dual role on immune response in inflammation of UC and tumor growth and progression of CRC.

Arterial stiffness modeling using variations of pulse transit time

In this paper, a finite elements (FE) modeling is used to model effects of the arterial stiffness on the different signal patterns of the pulse transit time (PTT). Four different breathing patterns of the same subject are measured with PTT signal and corresponding finite element model of the straight elastic artery is applied. The computational fluid structure model provides arterial elastic behavior and fitting procedure was applied in order to estimate stiffness of the artery. It was found that same elastic material characteristics were fitted for four different breathing patterns which validate this methodology for possible noninvasive determination of the arterial stiffness.

Numerical and experimental analysis of factors leading to suture dehiscence after Billroth II gastric resection

The main goal of this study was to numerically quantify risk of duodenal stump blowout after Billroth II (BII) gastric resection. Our hypothesis was that the geometry of the reconstructed tract after BII resection is one of the key factors that can lead to duodenal dehiscence. We used computational fluid dynamics (CFD) with finite element (FE) simulations of various models of BII reconstructed gastrointestinal (GI) tract, as well as non-perfused, ex vivo, porcine experimental models. As main geometrical parameters for FE postoperative models we have used duodenal stump length and inclination between gastric remnant and duodenal stump. Virtual gastric resection was performed on each of 3D FE models based on multislice Computer Tomography (CT) DICOM. According to our computer simulation the difference between maximal duodenal stump pressures for models with most and least preferable geometry of reconstructed GI tract is about 30%. We compared the resulting postoperative duodenal pressure from computer simulations with duodenal stump dehiscence pressure from the experiment. Pressure at duodenal stump after BII resection obtained by computer simulation is 4-5 times lower than the dehiscence pressure according to our experiment on isolated bowel segment. Our conclusion is that if the surgery is performed technically correct, geometry variations of the reconstructed GI tract by themselves are not sufficient to cause duodenal stump blowout. Pressure that develops in the duodenal stump after BII resection using omega loop, only in the conjunction with other risk factors can cause duodenal dehiscence. Increased duodenal pressure after BII resection is risk factor. Hence we recommend the routine use of Roux en Y anastomosis as a safer solution in terms of resulting intraluminal pressure. However, if the surgeon decides to perform BII reconstruction, results obtained with this methodology can be valuable.

TGF-Β as a Marker of Ulcerative Colitis and Disease Severity

Abstract Ulcerative colitis (UC) represents chronic inflammation of the large intestine. Immune response plays an important role in disease genesis and progression. Activated leukocytes secrete several cytokines that actively regulate the inflammatory response in UC. The aim of this study was to determine levels of cytokines IL-17, IL-27, IFN-γ and TGF-β in patients with UC and to test them as biomarkers for disease. The blood samples of 24 patients with ulcerative colitis without previous treatment and 37 healthy individuals were analyzed. Serum levels of IL-17, IL-27, IFN-γ and TGF-β were measured using sensitive enzyme-linked immunosorbent assay (ELISA) kits. Serum levels of IL-17, IL-27, IFN-γ and TGF-β were increased in patients with UC, compared to healthy controls (p=0.022; p=0.001; p=0.001; and p=0.002; respectively). Ratios of cytokines IL-27/IL-17, IFN-γ/TGF-β and IL-17/TGF-β were significantly higher in group of patients with UC (p=0.002; p=0.002; p=0.003; respectively). Serum value of TGF-β higher than 20 pg/ml presents a highly sensitive and specific marker for UC. We believe that increased production and predominance of immunosupressive TGF-β may represent compensatory mechanism for ongoing pro-inflammatory processes in UC.

Real-time monitoring of cytotoxic effects of electroporation on breast and colon cancer cell lines.

PURPOSE To study the effects of electroporation on different cell lines. MATERIAL The effects of electroporation on human breast cancer (MDA-MB-231), human colon cancer (SW-480 and HCT-116), human fibroblast cell line (MRC-5), primary human aortic smooth muscle cells (hAoSMC) and human umbilical vein endothelial cells (HUVEC) were studied. Real-time technology was used for cell viability monitoring. Acridine orange/ethidium bromide assay was applied for cell death type determination. A numerical model of electroporation has been proposed. RESULTS Electroporation induced inhibition of cell viability on dose (voltage) dependent way. The electroporation treatment 375-437.5Vcm-1 caused irreversible electroporation of cancer cells and reversible electroporation of healthy cells. The application of lower voltage rating (250Vcm-1) led to apoptosis as the predominant type of cell death, whereas the use of higher voltage (500Vcm-1) mainly caused necrosis. CONCLUSION Electroporation represents a promising method in cancer treatment. Different cancer cell lines had different response to the identical electroporation treatment. Electroporation 375-437.5Vcm-1 selectively caused permanent damage of cancer cells (SW-480), while healthy cells (MRC-5, hAoSM and HUVEC) recovered after 72h. The type of cell death is dependent of electroporation conditions. The proposed numerical model is useful for the analysis of phenomena related to electroporation treatment.

Modeling of Self-healing Materials with Nanocontainers Using Discrete and Continuum Methods

Corrosion degradation of materials is an important issue that leads to depreciation of investment goods. In production of materials a huge challenge is to design ‘smart’ synthetic systems that can actively re-establish the continuity and integrity of a damaged area. Nanocontainers represent new technology for smart nanocoating interfaces. This chapter describes the solutions based on an innovative integrated modeling approach, including nano- and macro-scale in the automotive, aerospace and biomedical industry. Two different modeling approaches, discrete and continuum, are used to investigate coating substrates that contain nanoscale defects with healing agents. Dissipative Particle Dynamics (DPD) method uses three forces: repulsive, dissipative and random forces, as well as additional forces which bound healing agents to a metal substrate. Finite Element Method (FEM) is continuum modeling method with different diffusivity and fluxes. The chapter includes the real case examples from industry with different concentrations of inhibitors inside the primer layer. These findings could be used for guidelines for formulating nanocomposite coatings and healing effects of the surfaces through the self-assembly of the particles into the defects.