Miljan Milosevic - Academia.edu (original) (raw)

Papers by Miljan Milosevic

2022 44th Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC), Jul 11, 2022

Computational and Mathematical Methods in Medicine

Stents made by different manufacturers must meet the requirements of standard in vitro mechanical... more Stents made by different manufacturers must meet the requirements of standard in vitro mechanical tests performed under different physiological conditions in order to be validated. In addition to in vitro research, there is a need for in silico numerical simulations that can help during the stent prototyping phase. In silico simulations have the ability to give the same stent responses as well as the potential to reduce costs and time needed to carry out experimental tests. The goal of this paper is to show the achievements of the computational platform created as a result of the EU-funded project InSilc, used for numerical testing of most standard tests for validation of preproduction bioresorbable vascular scaffolds (BVSs). Within the platform, an ad hoc simulation protocol has been developed based on the finite element (FE) analysis program PAK and user interface software CAD Field and Solid. Two different designs of two different stents have been numerically simulated using this...

Journal of the Serbian Society for Computational Mechanics

In this paper, we introduce an incremental formulation for large strains which is based on the no... more In this paper, we introduce an incremental formulation for large strains which is based on the nodal forces increments. It uses the linear strain increments at the current configuration as the fundamental strain measure, and consequently the stress increments which produce the nodal force increments. It does not assume any total strain and stress calculation according to total values of (large) displacements. It rather employs summation of internal finite element nodal forces during the incremental-iterative computational procedures. Solutions according to this new formulation are compared with a standard updated Lagrangian formulation, with the Green-Lagrangian strains evaluated using the total displacement derivatives with respect to the current reference configurations. The presented incremental-force based formulation can be considered as a generalization of the use of logarithmic strains.

Book of Proceedings: 1st International Conference on Chemo and BioInformatics, 2021

Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has b... more Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has become an essential part of the management of peritoneal carcinomatosis [1,2]. HIPEC is a cancer treatment procedure that involves filling the abdominal cavity with chemotherapy drugs that have been heated (also known as “hot chemotherapy”). HIPEC is performed after the surgical procedure of removing tumors or lesions from the abdominal area. In the past 30 years, the approach of combining CRS with minimal residual disease and intraperitoneal (IP) chemotherapy emerged as one with a potential for long-term survival. Multiple strategies have been employed to measure the functional peritoneal surface area and determine the required perfusion volume. For that purpose, we have developed a novel computational model (consisted from peritoneal cavity with immersed organs, generated from STL files), with precisely calculated functional peritoneal surface area and cavity volume (for each patient). ...

It is of enormous importance to have accurate electro-mechanical models for better understanding ... more It is of enormous importance to have accurate electro-mechanical models for better understanding of various heart diseases such as heart failure, cardiac arrhythmia, and cardiomyopathy. Muscles in the body are activated by electrical signals, transmitted from the nervous system to muscle cells, affecting the cell membranes potentials. Current flow through cell membrane contains ion currents of molecules such as sodium (Na+), potassium (K+) and calcium (Ca2+), which are critically important for muscle function. Calcium current and concentration inside the cell are the main cause of generating active stress within muscle fibers. In order to make computational models feasible for applications of such complex system, we introduced a Kojic Transport Model (KTM) for modelling physical fields, by formulating a KTM finite element for electrophysiology. In order to calculate calcium current and concentration within the cell, we coupled the KTM and the OHara-Rudy (ORd) membrane model. Electro...

The cardiac cycle consists of two periods: (1) diastole, during which the heart muscle relaxes an... more The cardiac cycle consists of two periods: (1) diastole, during which the heart muscle relaxes and refills with blood, and (2) systole, during which heart muscle contracts and pumps the blood out of the ventricle. Numerical modeling of the cardiac cycle can help to evaluate clinical scenarios and outcomes before experimental or clinical applications. In our work, we generated a solid and fluid left ventricle model from echocardiographic data and simulated a full cardiac cycle. Our semi-automatic model generation enables us to simulate cardiac behavior with patient-specific geometries. We simulated the behavior of the heart wall and blood separately, using<br> boundary surface, endocardium, as an interface between solid and fluid. We prescribed displacements to our solid model at the endocardium based on data from echocardiograms, and to our fluid model, we prescribed corresponding velocities at this same surface. We used our solid model with the experimental Holzapfel material...

Motion of the heart walls is achieved by mechanical forces generated within muscles in heart wall... more Motion of the heart walls is achieved by mechanical forces generated within muscles in heart wall activated by the nervous system. This motion further iduce blood flow as, mechanically, solid– fluid interaction. There is a number of physical fields within the left ventricle of heart, such as velocities of motion of solid and fluid and, fluid pressure; additionally, electrical potential field is directly coupled to biochemical process of transforming the chemical into mechanical energy and further to active forces for the body motion. In order to simulate ventricle behavior during a cardiac cycle, we have generated a novel computational model feasible for electrophysiology using concept of smeared physical fields (Kojic Transport Model, KTM) according to [1,2].<br> Applicability of this model is illustrated on a simple left ventricle parametrical model with inlet mitral and outlet aortic valve cross-sections. Further, we calculate smeared electrical field and cell membrane pote...

2021 IEEE 21st International Conference on Bioinformatics and Bioengineering (BIBE), 2021

Most cardiac diseases and disorders occur in the left ventricle. Numerical methods can give an in... more Most cardiac diseases and disorders occur in the left ventricle. Numerical methods can give an insight into the mechanical response of the left ventricle under different conditions, before the execution of clinical trials and experiments. Before we use the finite element method to analyze the behavior of the left ventricle, a geometrical model has to be generated. In our work, we generated a left ventricle model from echocardiographic data. We manually extracted contours of the inner and outer surface of the left ventricle and applied our algorithm to generate the 3D model. This semi-automatic model generation enables the usage of patient-specific geometries for finite element analysis of the left ventricle.

Diffusion in nanospace does not strictly obey to Fick’s law generally used in macroenvironment. D... more Diffusion in nanospace does not strictly obey to Fick’s law generally used in macroenvironment. Deviation from this law is due to surface effects, i.e. due to interaction between transported molecules and bounding surfaces. A hierarchical modeling approach which accounts for interface effects on the diffusion coefficient was introduced in Ziemys et al. (2011). The model employs molecular dynamics (MD) for calculation scaling functions to reduce the diffusion coefficient corresponding to “bulk” values. With this reduced diffusion coefficient, modeling is performed using the finite element method (FE) within an incremental iterative scheme. In this paper we summarize this hierarchical (multiscale) model and present its generalization to include adsorption at the walls. Also, we briefly discuss further possible applications of the multiscale modeling of diffusion through complex media with distributed solid constituents, as in case of polymers or biological fluids.

Computers in Biology and Medicine, 2018

One of the basic and vital processes in living organisms is mass exchange, which occurs on severa... more One of the basic and vital processes in living organisms is mass exchange, which occurs on several levels: it goes from blood vessels to cells and organelles within cells. On that path, molecules, as oxygen, metabolic products, drugs, etc. traverse different macro and micro environments-blood, extracellular/intracellular space, and interior of organelles; and also biological barriers such as *

Journal of Controlled Release, 2018

Metastatic disease is a major cause of mortality in cancer patients. While many drug delivery str... more Metastatic disease is a major cause of mortality in cancer patients. While many drug delivery strategies for anticancer therapeutics have been developed in preclinical studies of primary tumors, the drug delivery properties of metastatic tumors have not been sufficiently investigated. Therapeutic efficacy hinges on efficient drug permeation into the tumor microenvironment, which is known to be heterogeneous thus potentially making drug permeation heterogeneous, also. In this study, we have identified that 4T1 liver metastases, treated with pegylated liposomal doxorubicin, have unfavorable and heterogeneous transport of doxorubicin. Our drug extravasation results differ greatly from analogous studies with 4T1 tumors growing in the primary site. A probabilistic tumor population model was developed to estimate drug permeation efficiency and drug kinetics of liver metastases by integrating the transport and structural properties of tumors and delivered drugs. The results demonstrate significant heterogeneity in metastases with regard to transport properties of doxorubicin within the same animal model, and even within the same organ. These results also suggest that the degree of heterogeneity depends on the stage of tumor progression and that differences in transport properties can define transport-based tumor phenotypes. These findings may have valuable clinical implications by illustrating that therapeutic agents can permeate and eliminate metastases of "less resistant" transport phenotypes, while sparing tumors with more "resistant" transport properties. We anticipate that these results could challenge the current paradigm of drug delivery into metastases, highlight potential caveats for therapies that may alter tumor perfusion, and deepen our understanding of the emergence of drug transport-based therapeutic resistance.

Computer Methods in Applied Mechanics and Engineering, 2017

One of the key processes in living organisms is mass transport occurring from blood vessels to ti... more One of the key processes in living organisms is mass transport occurring from blood vessels to tissues for supplying tissues with oxygen, nutrients, drugs, immune cells, and-in the reverse direction-transport of waste products of cell metabolism to blood vessels. The mass exchange from blood vessels to tissue and vice versa occurs through blood vessel walls. This vital process has been investigated experimentally over centuries, and also in the last decades by the use of computational methods. Due to geometrical and functional complexity and heterogeneity of capillary systems, it is however not feasible to model in silico individual capillaries (including *

2015 IEEE 15th International Conference on Bioinformatics and Bioengineering (BIBE), 2015

In this report we summarize computational models for convective and diffusive drug transport with... more In this report we summarize computational models for convective and diffusive drug transport within small blood vessels (capillaries) and tissue. The presented methodology is primarily focused on drug transport via micro-nanoparticles designed for nanotherapeutics in cancer. Our original multiscale hierarchical models couple nanoscale molecular dynamics (MD) and macroscale continuum finite element (FE) discretization. The convective part relies on a FE solution of the solid-fluid interaction problem of moving bodies within fluid, with a remeshing procedure. In diffusion, MD is used to evaluate the effective diffusivity of a porous continuum, where the physico-chemical interaction between transported molecules and microstructural surface is included, and the mass release curves are considered as the constitutive curves. Several representative examples illustrate effectiveness of our methodology and developed software PAK.

Journal of Controlled Release, 2015

Although nanotherapeutics can be advantageous over free chemotherapy, the benefits of drug vector... more Although nanotherapeutics can be advantageous over free chemotherapy, the benefits of drug vectors can vary from patient to patient based on differences in tumor microenvironments. Although systemic pharmacokinetics (PK) of drugs is considered as the major determinant of its efficacy in clinics, recent clinical and basic research indicates that tumor-based PK can provide better representation of therapeutic efficacy. Here, we have studied the role of the tumor extravascular tissue in the extravasation kinetics of doxorubicin (DOX), delivered by pegylated liposomes (PLD), to murine lung (3LL) and breast (4T1) tumors. We found that phenotypically different 3LL and 4T1 tumors shared the similar systemic PK, but DOX extravasation in the tumor extravascular tissue was substantially different. Liquid chromatography-mass spectrometry (LC-MS) measurements showed that DOX fluorescence imaged by fluorescence microscopy could be used as a marker to study tumor microenvironment PK, providing an excellent match to DOX kinetics in tumor tissues. Our results also suggest that therapeutic responses can be closely related to the interplay of concentration levels and exposure times in extravascular tissue of tumors. Finally, the computational model of capillary drug transport showed that internalization of drug vectors was critical and could lead to 2-3 orders of magnitude more efficient drug delivery into the extravascular tissue, compared to noninternalized localization of drug vectors, and explaining the differences in therapeutic efficacy between the 3LL and 4T1 tumors. These results show that drug transport and partitioning characteristics can be phenotype-and microenvironment-dependent and are highly important in drug delivery and therapeutic efficacy.

Nanofluidic systems are found naturally in geological formations and biology, but they also are i... more Nanofluidic systems are found naturally in geological formations and biology, but they also are implemented in technology, where mass exchange is the governing process. Here we employed recently developed multiscale model for diffusion in nanoconfinement to understand passive transport regimes in nanochannels. Hew we use a critical parameter that may help to differentiate different diffusion regimes in nanochannels. Our study shows a new insight into diffusive mass transport through nanoconfined structures and establishes relations among geometry, interface effects and mass transport kinetics.

Computers in Biology and Medicine, 2015

Circulating tumor cells (CTCs) are known to be a harbinger of cancer metastasis. The CTCs are kno... more Circulating tumor cells (CTCs) are known to be a harbinger of cancer metastasis. The CTCs are known to circulate as individual cells or as a group of interconnected cells called CTC clusters. Since both single CTCs and CTC clusters have been detected in venous blood samples of cancer patients, they needed to traverse at least one capillary bed when crossing from arterial to venous circulation. The diameter of a typical capillary is about 7 μm, whereas the size of an individual CTC or CTC clusters can be greater than 20 μm and thus size exclusion is believed to be an important factor in the capillary arrest of CTCs-a key early event in metastasis. To examine the biophysical conditions needed for capillary arrest, we have developed a custom-built viscoelastic solid-fluid 3D computational model that enables us to calculate, under physiological conditions, the maximal CTC diameter that will pass through the capillary. We show that large CTCs and CTC clusters can successfully cross capillaries if their stiffness is relatively small. Specifically, under physiological conditions, a 13 μm diameter CTC passes through a 7 μm capillary only if its stiffness is less than 500 Pa and conversely, for a stiffness of 10 Pa the maximal passing diameter can be as high as 140 μm, such as for a cluster of CTCs. By exploring the parameter space, a relationship between the capillary blood pressure gradient and the CTC mechanical properties (size and stiffness) was determined. The presented computational platform and the resulting pressure-size-stiffness relationship can be employed as a tool to help study the biomechanical conditions needed for capillary arrest of CTCs and CTC clusters, provide predictive capabilities in disease progression based on biophysical CTC parameters, and aid in the rational design of sizebased CTC isolation technologies where CTCs can experience large deformations due to high pressure gradients.

Drug delivery, Jan 2, 2015

Over the last decade, nanotherapeutics gained increasingly important role in drug delivery becaus... more Over the last decade, nanotherapeutics gained increasingly important role in drug delivery because of their frequently beneficial pharmacokinetics (PK) and lower toxicity when compared to classical systemic drug delivery. In view of therapeutic payload delivery, convective transport is crucial for systemic distribution via circulatory system, but the target domain is tissue outside vessels where transport is governed by diffusion. Here, we have computationally investigated the understudied interplay of physical transports to characterize PK of payload of nanotherapeutics. The analysis of human vasculature tree showed that convective transport is still 5 times more efficient than diffusion suggesting that circulating and payload releasing drug vectors can contribute mostly to systemic delivery. By comparing payload delivery using systemic circulation and drug vectors to microenvironment, internalized vectors were the most efficient and showed Area under the Curve almost 100 higher th...

Contemporary Materials, 2013

Diffusion in natural, technological and biological systems is very common and most important proc... more Diffusion in natural, technological and biological systems is very common and most important process. Within these systems, which contain complex media, diffusion may depend not only on internal geometry, but also on the chemical interactions between solid phase and transported particles. Modeling remains a challenge due to this complexity. Here we first present a new hierarchical multiscale microstructural model for diffusion within complex media that incorporates both the internal geometry of complex media and the interaction between diffusing particles and surfaces of microstructures. Hierarchical modeling approach, which was introduced in [1], is employed to construct a continuum diffusion model based on a novel numerical homogenization procedure. Using this procedure, we evaluate constitutive material parameters of the continuum model, which include: equivalent bulk diffusion coefficients and the equivalent distances from the solid surface. Here, we examined diffusion of glucose through water using the following two geometrical/material configurations: silica nanofibers, and a complex internal structure consisting of randomly placed nanospheres and nanofibers. This new approach, consisting of microstructural model, numerical homogenization and continuum model, offer a new platform for modeling diffusion within complex media, capable of connecting micro and macro scales.

Multiscale Modeling in Biomechanics and Mechanobiology, 2014

A review of computational procedures for convective and diffusive transport, developed by the aut... more A review of computational procedures for convective and diffusive transport, developed by the authors, is presented in this chapter. The presented finite element computational framework is directed to transport within capillaries and tissue. The convective transport includes modeling of motion of deformable bodies within fluid flow. It is based on a strong coupling concept and remeshing procedure. It was found by the authors that this approach has advantages in reliability and accuracy with respect to others available in literature, although it is not computationally efficient. A hierarchical multiscale model for diffusion couples molecular dynamics and continuum FE method by evaluating equivalent continuum diffusive parameters; these parameters include commonly used diffusion coefficients, but also parameters which account for physicochemical interactions between diffusing molecules and microstructural solid surfaces. A numerical homogenization is used in this multiscale model. Coupled convective and diffusive transport is also considered. A number of typical solved examples illustrate generality, robustness, and accuracy of the presented computational methodology.