SGABU computational platform for multiscale modeling:Bridging the gap between education and research

BACKGROUND AND OBJECTIVE: In accordance with the latest aspirations in the field of bioengineering, there is a need to create a web accessible, but powerful cloud computational platform that combines datasets and multiscale models related to bone modeling, cancer, cardiovascular diseases and tissue engineering. The SGABU platform may become a powerful information system for research and education that can integrate data, extract information, and facilitate knowledge exchange with the goal of creating and developing appropriate computing pipelines to provide accurate and comprehensive biological information from the molecular to organ level. METHODS: The datasets integrated into the platform are obtained from experimental and/or clinical studies and are mainly in tabular or image file format, including metadata. The implementation of multiscale models, is an ambitious effort of the platform to capture phenomena at different length scales, described using partial and ordinary differential equations, which are solved numerically on complex geometries with the use of the finite element method. The majority of the SGABU platform's simulation pipelines are provided as Common Workflow Language (CWL) workflows. Each of them requires creating a CWL implementation on the backend and a user-friendly interface using standard web technologies. Platform is available at https://sgabu-test.unic.kg.ac.rs/login. RESULTS: The main dashboard of the SGABU platform is divided into sections for each field of research, each one of which includes a subsection of datasets and multiscale models. The datasets can be presented in a simple form as tabular data, or using technologies such as Plotly.js for 2D plot interactivity, Kitware Paraview Glance for 3D view. Regarding the models, the usage of Docker containerization for packing the individual tools and CWL orchestration for describing inputs with validation forms and outputs with tabular views for output visualization, interactive diagrams, 3D views and animations. CONCLUSIONS: In practice, the structure of SGABU platform means that any of the integrated workflows can work equally well on any other bioengineering platform. The key advantage of the SGABU platform over similar efforts is its versatility offered with the use of modern, modular, and extensible technology for various levels of architecture.</p

SGABU computational platform for multiscale modeling: Bridging the gap between education and research

In accordance with the latest aspirations in the field of bioengineering, there is a need to create a web accessible, but powerful cloud computational platform that combines datasets and multiscale models related to bone modeling, cancer, cardiovascular diseases and tissue engineering. The SGABU platform may become a powerful information system for research and education that can integrate data, extract information, and facilitate knowledge exchange with the goal of creating and developing appropriate computing pipelines to provide accurate and comprehensive biological information from the molecular to organ level.Publishe

Development of right ventricular implants in pulmonary hypertension

Pulmonary hypertension is defined as an increase in pulmonary arterial pressure at values higher than the normal ones. This increase has as a direct consequence of causing right ventricular pressure overload, which initially leads to hypertrophy and ultimately to right heart failure or even death. Indeed, pulmonary arterial hypertension (PAH) is a lethal disease with high rates of mortality and morbidity. Also, if not diagnosed and treated promptly, then average survival is only 2.8 years. Nonetheless, prognosis and diagnosis is still determined by the hypertrophy and by the right ventricular dilation and dysfunction. There are three main therapeutic options for the treatment of pulmonary hypertension, pharmacological treatments, mechanical support of the right ventricle (using special devices), and the use of biomaterials and implants. Regarding the latter option, a thorough literature review shows that there is no scientific documentation reporting on implants developed for use in right ventricular myocardium after pulmonary hypertension. The presentstudy aims at covering this gap by proposing a Road Map for the development of biomaterials for implants that can be used to treat (prevent, treat) pulmonary hypertension. Thus, this investigation comprises two distinct stages. The first one concerns the selection, qualification and optimization of a biomaterial that can be a candidate for being used for this purpose. The second one highlights the development (in terms of biology, surgery practice and performance, microstructure, chemistry, and mechanics) of the interface and the interactions between the implant and the outer surface of the myocardium, where the membrane is placed, as a major issue for predicting and understanding the performance of a biomaterial in the treatment of the disease, following the appropriate medicalprotocol proposed by the surgeon as far as its application in the heart is concerned. In the light of the specific application in the present case and the level of the research undertaken in this study, the most suitable geometry of the biomaterial was selected to be that of a membrane. Then, eight qualification criteria were defined, which must satisfy a biomaterial in order to be selected as candidate for use in the treatment of the disease. These are (1) the ability to create a membrane, (2) the good quality of the membrane, (3) the flexibility in order to be able to wrap around the epicardial tissue, (4) the tuning ability to regulate the mechanical properties in order to approach those of the cardiac tissue, (5) the tuning ability to regulate the thickness, (6) neutral pH, (7) in vitro and in vivo biocompatibility, and (8) biodegradability within a specific period of time. A series of hydrogels were produced, starting with PEG (poly (ethylene glycol)) and its derivatives ofPEGSDA (PEG sebacate diacrylate) and OPF (oligo poly (ethylene glycol) fumarate), followed by hydrogels of natural polysaccharides based on alginic acid and chitosan. The hydrogels based on PEG and alginic acid did not meet the qualification criteria and were, therefore, rejected from further consideration and experimentation. However, chitosan hydrogels showed better behavior. Therefore, various preparation methods were tested in order to produce a membrane that meets the qualification criteria. The parameters tested were the molecular weight (medium and low molecular weight chitosan was used), the neutralization solution (NaOH, KOH, β-GP), and theneutralization procedure (immersion or drop wise). Any combination of these three factors affects the mechanism of hydrogel formation and therefore the quality of the final product. The membrane with the optimal properties was prepared by the gelation process, using NaOH solution as a neutralizing agent without solvent evaporation. The properties of this membrane, which met the selection criteria, were determined experimentally. The determination of the degree of deacetylation, of the structural features of the membrane, by using X-ray diffraction and infrared (FT-IR) spectroscopy, of the microstructure and the texture (porosity) of the membrane, of the thermal properties, the sorption ability in PBS and water at 37 ° C, and the mechanical properties, was experimentally carried out. The mechanical properties were measured by tensile strength experiments in dry and wet environment as well as after the membrane immersion in blood plasma and PBS at 37° C for estimating the degradation of mechanical properties in a physiological environment over time, and by dynamic mechanical analysis (DMA) measurements in a dry and wet environment, to determine the storage modulus (E ') and of the damping factor (tanδ). The above properties were measured in order to evaluate whether this membrane mimics the properties ofthe heart tissue. The results showed that the physicochemical properties and the microstructure allow the membrane to be regarded as a candidate for use in the particular application, while its mechanical properties are in good agreement with the values of the myocardial tissue. Then, the interface developed between the selected membrane and cells or cardiac tissue was studied. Invitro biological tests were performed in fibroblast cell culture (NIH3T3). The results showed evidence of viability and growth of fibroblasts in the chitosan membrane, suggesting the biocompatibility of the membrane. Then, in vivo tests, by implanting the membrane in Wistar rats, were conducted. The results showed that a surgeon can easily and reliably handle the membrane, the membrane was positioned accurately around the heart and remained firmly in place within the period of implantation (30 days), without causing any problems or death in animals. There was also evidence of degradation. After the animals euthanasia, the foreign body response recorded the bestpossible biological response to the implanted material, where a significant reduction in inflammatory and a prominent increase of newly formed vessels were recorded. Then, the chemistry of the interface between the membrane and the myocardial tissue after implantation of 2 and 7 days was studied. The heart tissue wrapped around with membrane was obtained from the animals and theinterface was separated. The detached surfaces were examined by infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy (XPS). The experimental findings were interpreted with the aid of results calculated theoretically by using the density functional theory (DFT) according to the B3LYP / 6-31G method. Both experimental and theoretical results suggested a strong interaction between membrane and tissue, attributed to ionic and hydrogen bonds. Finally, computational modeling was performed by developing a realistic simulation model of the human heart, in order to evaluate the effect of the membrane prepared on wall stress, deformation, and displacement inthe case of pulmonary hypertension. Before solving the problem, the three-dimensional geometry of the right ventricle was first constructed, followed by creating fluid and solid mesh and finally by defining the boundary conditions and the properties of the fluid and solid ventricular wall. Various thicknesses of membranes (1, 2, 3 mm) and Young modulus (0.3 - 0.7 MPa) were tested. The work ends with a discussion, the conclusions, and proposals for future research

Isolation of an ES-Derived Cardiovascular Multipotent Cell Population Based on VE-Cadherin Promoter Activity

Embryonic Stem (ES) or induced Pluripotent Stem (iPS) cells are important sources for cardiomyocyte generation, targeted for regenerative therapies. Several in vitro protocols are currently utilized for their differentiation, but the value of cell-based approaches remains unclear. Here, we characterized a cardiovascular progenitor population derived during ES differentiation, after selection based on VE-cadherin promoter (Pvec) activity. ESCs were genetically modified with an episomal vector, allowing the expression of puromycin resistance gene, under Pvec activity. Puromycin-surviving cells displayed cardiac and endothelial progenitor cells characteristics. Expansion and self-renewal of this cardiac and endothelial dual-progenitor population (CEDP) were achieved by Wnt/β-catenin pathway activation. CEDPs express early cardiac developmental stage-specific markers but not markers of differentiated cardiomyocytes. Similarly, CEDPs express endothelial markers. However, CEDPs can undergo differentiation predominantly to cTnT+ (~47%) and VE-cadherin+ (~28%) cells. Transplantation of CEDPs in the left heart ventricle of adult rats showed that CEDPs-derived cells survive and differentiate in vivo for at least 14 days after transplantation. A novel, dual-progenitor population was isolated during ESCs differentiation, based on Pvec activity. This lineage can self-renew, permitting its maintenance as a source of cardiovascular progenitor cells and constitutes a useful source for regenerative approaches

Medium-term Electrophysiologic Effects of a Cellularized Scaffold Implanted in Rats After Myocardial Infarction

Background Cardiac repair strategies are being evaluated for myocardial infarctions, but the safety issues regarding their arrhythmogenic potential remain unresolved. By utilizing the in-vivo rat model, we have examined the medium-term electrophysiologic effects of a biomaterial scaffold that has been cellularized with spheroids of human adipose tissue, derived from mesenchymal stem cells and umbilical vein endothelial cells. Methods Mesenchymal stem cells, which exhibit adequate differentiation capacity, were co-cultured with umbilical vein endothelial cells and were seeded on an alginate based scaffold. After in-vitro characterization, the cellularized scaffold was implanted in (n=15) adult Wistar rats 15 min post ligation of the left coronary artery, with an equal number of animals serving as controls. Two weeks thereafter, monophasic action potentials were recorded and activation-mapping was performed with a multi-electrode array. An arrhythmia score for inducible ventricular tachyarrhythmias was calculated after programmed electrical stimulation. Results The arrhythmia score was comparable between the treated animals and controls. No differences were detected in the local conduction at the infarct border and in the voltage rise in monophasic action potential recordings. Treatment did not affect the duration of local repolarization, but tended to enhance its dispersion. Conclusions The fabricated bi-culture cellularized scaffold displayed favorable properties after in-vitro characterization. Medium-term electrophysiologic assessment after implantation in the infarcted rat myocardium revealed low arrhythmogenic potential, but the long-term effects on repolarization dispersion will require further investigation

Prolonged intra-myocardial growth hormone administration ameliorates post-infarction electrophysiologic remodeling in rats.

Experimental studies indicate improved ventricular function after treatment with growth hormone (GH) post-myocardial infarction, but its effect on arrhythmogenesis is unknown. Here, we assessed the medium-term electrophysiologic remodeling after intra-myocardial GH administration in (n = 33) rats. GH was released from an alginate scaffold, injected around the ischemic myocardium after coronary ligation. Two weeks thereafter, ventricular tachyarrhythmias were induced by programmed electrical stimulation. Monophasic action potentials were recorded from the infarct border, coupled with evaluation of electrical conduction and repolarization from a multi-electrode array. The arrhythmia score was lower in GH-treated rats than in alginate-treated rats or controls. The shape and the duration of the action potential at the infarct border were preserved, and repolarization-dispersion was attenuated after GH; moreover, voltage rise was higher and activation delay was shorter. GH normalized also right ventricular parameters. Intra-myocardial GH preserved electrical conduction and repolarization-dispersion at the infarct border and decreased the incidence of induced tachyarrhythmias in rats post-ligation. The long-term antiarrhythmic potential of GH merits further study

A Combined Computational and Experimental Analysis of PLA and PCL Hybrid Nanocomposites 3D Printed Scaffolds for Bone Regeneration

A combined computational and experimental study of 3D-printed scaffolds made from hybrid nanocomposite materials for potential applications in bone tissue engineering is presented. Polycaprolactone (PCL) and polylactic acid (PLA), enhanced with chitosan (CS) and multiwalled carbon nanotubes (MWCNTs), were investigated in respect of their mechanical characteristics and responses in fluidic environments. A novel scaffold geometry was designed, considering the requirements of cellular proliferation and mechanical properties. Specimens with the same dimensions and porosity of 45% were studied to fully describe and understand the yielding behavior. Mechanical testing indicated higher apparent moduli in the PLA-based scaffolds, while compressive strength decreased with CS/MWCNTs reinforcement due to nanoscale challenges in 3D printing. Mechanical modeling revealed lower stresses in the PLA scaffolds, attributed to the molecular mass of the filler. Despite modeling challenges, adjustments improved simulation accuracy, aligning well with experimental values. Material and reinforcement choices significantly influenced responses to mechanical loads, emphasizing optimal structural robustness. Computational fluid dynamics emphasized the significance of scaffold permeability and wall shear stress in influencing bone tissue growth. For an inlet velocity of 0.1 mm/s, the permeability value was estimated at 4.41 × 10−9 m2, which is in the acceptable range close to human natural bone permeability. The average wall shear stress (WSS) value that indicates the mechanical stimuli produced by cells was calculated to be 2.48 mPa, which is within the range of the reported literature values for promoting a higher proliferation rate and improving osteogenic differentiation. Overall, a holistic approach was utilized to achieve a delicate balance between structural robustness and optimal fluidic conditions, in order to enhance the overall performance of scaffolds in tissue engineering applications