Machine Learning Model for Prediction of Development of Cancer Stem Cell Subpopulation in Tumurs Subjected to Polystyrene Nanoparticles.

Cancer stem cells (CSCs) play a key role in tumor progression, as they are often responsible for drug resistance and metastasis. Environmental pollution with polystyrene has a negative impact on human health. We investigated the effect of polystyrene nanoparticles (PSNPs) on cancer cell stemness using flow cytometric analysis of CD24, CD44, ABCG2, ALDH1 and their combinations. This study uses simultaneous in vitro cell lines and an in silico machine learning (ML) model to predict the progression of cancer stem cell (CSC) subpopulations in colon (HCT-116) and breast (MDA-MB-231) cancer cells. Our findings indicate a significant increase in cancer stemness induced by PSNPs. Exposure to polystyrene nanoparticles stimulated the development of less differentiated subpopulations of cells within the tumor, a marker of increased tumor aggressiveness. The experimental results were further used to train an ML model that accurately predicts the development of CSC markers. Machine learning, especially genetic algorithms, may be useful in predicting the development of cancer stem cells over time.

AI-Driven Optimization of PCL/PEG Electrospun Scaffolds for Enhanced In Vivo Wound Healing.

Here, an artificial intelligence (AI)-based approach was employed to optimize the production of electrospun scaffolds for in vivo wound healing applications. By combining polycaprolactone (PCL) and poly(ethylene glycol) (PEG) in various concentration ratios, dissolved in chloroform (CHCl3) and dimethylformamide (DMF), 125 different polymer combinations were created. From these polymer combinations, electrospun nanofiber meshes were produced and characterized structurally and mechanically via microscopic techniques, including chemical composition and fiber diameter determination. Subsequently, these data were used to train a neural network, creating an AI model to predict the optimal scaffold production solution. Guided by the predictions and experimental outcomes of the AI model, the most promising scaffold for further in vitro analyses was identified. Moreover, we enriched this selected polymer combination by incorporating antibiotics, aiming to develop electrospun nanofiber scaffolds tailored for in vivo wound healing applications. Our study underscores three noteworthy conclusions: (i) the application of AI is pivotal in the fields of material and biomedical sciences, (ii) our methodology provides an effective blueprint for the initial screening of biomedical materials, and (iii) electrospun PCL/PEG antibiotic-bearing scaffolds exhibit outstanding results in promoting neoangiogenesis and facilitating in vivo wound treatment.

Modeling 5-FU-Induced Chemotherapy Selection of a Drug-Resistant Cancer Stem Cell Subpopulation.

(1) Background: Cancer stem cells (CSCs) are a subpopulation of cells in a tumor that can self-regenerate and produce different types of cells with the ability to initiate tumor growth and dissemination. Chemotherapy resistance, caused by numerous mechanisms by which tumor tissue manages to overcome the effects of drugs, remains the main problem in cancer treatment. The identification of markers on the cell surface specific to CSCs is important for understanding this phenomenon. (2) Methods: The expression of markers CD24, CD44, ALDH1, and ABCG2 was analyzed on the surface of CSCs in two cancer cell lines, MDA-MB-231 and HCT-116, after treatment with 5-fluorouracil (5-FU) using flow cytometry analysis. A machine learning model (ML)-genetic algorithm (GA) was used for the in silico simulation of drug resistance. (3) Results: As evaluated through the use of flow cytometry, the percentage of CD24-CD44+ MDA-MB-231 and CD44, ALDH1 and ABCG2 HCT-116 in a group treated with 5-FU was significantly increased compared to untreated cells. The CSC population was enriched after treatment with chemotherapy, suggesting that these cells have enhanced drug resistance mechanisms. (4) Conclusions: Each individual GA prediction model achieved high accuracy in estimating the expression rate of CSC markers on cancer cells treated with 5-FU. Artificial intelligence can be used as a powerful tool for predicting drug resistance.

InSilc Computational Tool for In Silico Optimization of Drug-Eluting Bioresorbable Vascular Scaffolds.

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 integrated tool, and the results have been demonstrated. The following standard tests have been performed: longitudinal tensile strength, local compression, kinking, and flex 1-3. Strut thickness and additional pocket holes (slots) in two different scaffolds have been used as representative parameters for comparing the mechanical characteristics of the stents (AB-BVS vs. AB-BVS-thinner and PLLA-prot vs. PLLA-plot-slot). The AB-BVS-thinner prototype shows better overall stress distribution than the AB-BVS, while the PLLA-prot shows better overall stress distribution in comparison to the PLLA-plot-slot. In all cases, the values of the maximum effective stresses are below 220 MPa-the value obtained by in vitro experiment. Despite the presented results, additional considerations should be included before the proposed software can be used as a validation tool for stent prototyping.

Virtual ABI: A computationally derived ABI index for noninvasive assessment of femoro-popliteal bypass surgery outcome.

BACKGROUND AND OBJECTIVE: Peripheral arterial disease of the lower limbs, which affects 12-14% of the population, is often treated by bypassing a blocked portion of the vessel. Due to the limited ability of clinicians to predict the outcome of a selected bypass strategy, the five-year graft occlusion ranges from 50% to 90%, with a 20% risk of amputation in the first 5 years after the surgery. The aim of this study was to develop a computational procedure that could enable surgeons to reduce negative effects by assessing patient-specific response to the available surgical strategies. METHODS: The Virtual ABI assumes patient-specific finite element modeling of patients' hemodynamics from routinely acquired medical scans of lower limbs. The key contribution of this study is a novel approach for prescribing boundary conditions, which combines noninvasive preoperative measurements and results of numerical simulations. RESULTS: The validation performed on six follow-up cases indicated high reliability of the Virtual ABI, since the correlation with the experimentally measured values of ankle-brachial index was R² = 0.9485. CONCLUSION: The initial validation showed that the proposed Virtual ABI is a noninvasive procedure that could assist clinicians to find an optimal strategy for treating a particular patient by varying bypass length, choosing adequate diameter, position and shape.

In vitro and in silico testing of partially and fully bioresorbable vascular scaffold.

Coronary artery disease (CAD), one of the leading causes of death globally, occurs due to the growth of atherosclerotic plaques in the coronary arteries, causing lesions which restrict the flow of blood to the myocardium. Percutaneous transluminal coronary angioplasty (PTCA), including balloon angioplasty and coronary stent deployment is a standard clinical invasive treatment for CAD. Coronary stents are delivered using a balloon catheter inserted across the lesion. The balloon is inflated to a nominal pressure, opening the occluded artery, deploying the stent and improving the flow of blood to the myocardium. All stent manufacturers have to perform standard in vitro mechanical testing under different physiological conditions. In this study, partially and fully bioresorbable vascular scaffolds (BVS) from Boston Scientific Limited have been examined in vitro and in silico for three different test methods: inflation, radial compression and crush resistance. We formulated a material model for poly-L-lactic acid (PLLA) and implemented it into our in-house software tool. A comparison of the different experimental results is presented in the form of graphs showing displacement-force curves, diameter - load curves or diameter - pressure curves. There is a strong correlation between simulation and real experiments with a coefficient of determination (R2) > 0.99 and a correlation coefficient (R) > 0.99. This preliminary study has shown that in-silico tests can mimic the applicable ISO standards for mechanical in vitro stent testing, providing the opportunity to use data generated using in-silico testing to partially or fully replacing the mechanical testing required for regulatory submission.

Application of in silico Platform for the Development and Optimization of Fully Bioresorbable Vascular Scaffold Designs.

Bioresorbable vascular scaffolds (BVS), made either from polymers or from metals, are promising materials for treating coronary artery disease through the processes of percutaneous transluminal coronary angioplasty. Despite the opinion that bioresorbable polymers are more promising for coronary stents, their long-term advantages over metallic alloys have not yet been demonstrated. The development of new polymer-based BVS or optimization of the existing ones requires engineers to perform many very expensive mechanical tests to identify optimal structural geometry and material characteristics. in silico mechanical testing opens the possibility for a fast and low-cost process of analysis of all the mechanical characteristics and also provides the possibility to compare two or more competing designs. In this study, we used a recently introduced material model of poly-l-lactic acid (PLLA) fully bioresorbable vascular scaffold and recently empowered numerical InSilc platform to perform in silico mechanicals tests of two different stent designs with different material and geometrical characteristics. The result of inflation, radial compression, three-point bending, and two-plate crush tests shows that numerical procedures with true experimental constitutive relationships could provide reliable conclusions and a significant contribution to the optimization and design of bioresorbable polymer-based stents.

An innovative method for precise lymph node detection before surgical treatment in breast cancer.

OBJECTIVE: To describe a new method of 3D interactive modeling which integrates images obtained by separate SPET and multi slice computed tomography (MSCT) modalities using an original software in order to better localize SNL in BC patients. SUBJECTS AND METHODS: We used technetium-99m-colloid rhenium sulphate for identifying SNL in seven patients with BC. Markers were made of lead pearls wrapped with cotton wool soaked in 99mTc-pertechnetate and placed on the skin of the patients forming of a triangle. Using an original software, two separate 3D models were made after SPET and MSCT imaging and then merged into a hybrid 3D model which enabled precise visualization and localization of the SNL. RESULTS: In all cases the position of the SNL established by our method was successfully verified using a gamma probe. Duration of SNL identification and extirpation were significantly reduced in less than 10 minutes per patient. The reproducibility of this method was confirmed by precise identification and biopsy of the SNL. CONCLUSION: We found this integrated SPET/MSCT 3D model to be much faster and easier to use as compared with the "classic" method, which was based on a radioactivity detection probe. In addition, our method was reproducible, accurate and of low cost. In other words, the method described in this paper could be very useful for health facilities with modest budget, because it obviates the need for buying expensive integrated SPET/MSCT hybrid imaging systems while detecting SNLs more accurately and in shorter time.

Morphological and Biomechanical Features in Abdominal Aortic Aneurysm with Long and Short Neck-Case-Control Study in 64 Abdominal Aortic Aneurysms.

BACKGROUND: Both, open and endovascular, procedures are related to higher complication rate in abdominal aortic aneurysm (AAA) with shorter neck. Previous study showed that long-neck AAA might have lower risk of rupture. Estimation of biomechanical forces in AAA improves rupture risk assessment. The aim of this study was to compare morphological features and biomechanical forces in the short- and long-neck AAA with threshold of 15 mm. METHODS: Digital Imaging and Communication in Medicine images of 64 aneurysms were prospectively collected and analyzed in a case-control study. Using commercially available software, Peak wall Stress (PWS) and Rupture Risk Equivalent Diameter (RRED) were determined. Difference between the maximal aneurysm diameter (MAD) and RRED was calculated and expressed as an absolute and relative (percentage of the MAD) value. In addition, volume of intraluminal thrombus (ILT) was calculated and expressed relative to AAA volume. RESULTS: Study included 64 AAA divided in group with long (36, 56.25%), and short (28, 43.75%) neck. There was no correlation between neck length and MAD, PWS, and RRED (P = 0.646, P = 0.421, and P = 0.405, respectively). Relative ILT volume was greater in the short-neck aneurysms (P = 0.033). Relative difference between RRED and MAD was -4% and -14.8% in short- and long-neck aneurysms, respectively (P = 0.029). The difference between RRED and MAD was positive in 14/28 patients (50%) with short neck and in 6/35 patients (17.14%) with long neck (P = 0.011). CONCLUSIONS: Based on our biomechanical analysis, in AAA with neck longer than 15 mm rupture risk might be lower than the risk estimated by its diameter. It might be explained with lower relative volume of ILT.

Numerical simulation of blood flow and plaque progression in carotid-carotid bypass patient specific case.

This study describes computer simulation of blood flow and plaque progression pattern in a patient who underwent surgical treatment for infected carotid prosthetic tube graft using carotid-carotid cross-over bypass. The 3D blood flow is governed by the Navier-Stokes equations, together with the continuity equation. Mass transfer within the blood lumen and through the arterial wall is coupled with the blood flow and is modelled by the convection-diffusion equation. Low-density lipoprotein (LDL) transport in lumen of the vessel is described by Kedem-Katchalsky equations. The inflammatory process is solved using three additional reaction-diffusion partial differential equations. Calculation based on a computer simulation showed that flow distribution in the left carotid artery (CA) was around 40-50% of the total flow in the right common CA. Also, the left CA had higher pressure gradient after surgical intervention. Plaque progression simulation predicted development of the atherosclerotic plaque in the position of the right common CA and the left internal CA. A novel way of atherosclerotic plaque progression modelling using computer simulation shows a potential clinical benefit with significant impact on the treatment strategy optimization.

Occlusal load distribution through the cortical and trabecular bone of the human mid-facial skeleton in natural dentition: a three-dimensional finite element study.

Understanding of the occlusal load distribution through the mid-facial skeleton in natural dentition is essential because alterations in magnitude and/or direction of occlusal forces may cause remarkable changes in cortical and trabecular bone structure. Previous analyses by strain gauge technique, photoelastic and, more recently, finite element (FE) methods provided no direct evidence for occlusal load distribution through the cortical and trabecular bone compartments individually. Therefore, we developed an improved three-dimensional FE model of the human skull in order to clarify the distribution of occlusal forces through the cortical and trabecular bone during habitual masticatory activities. Particular focus was placed on the load transfer through the anterior and posterior maxilla. The results were presented in von Mises stress (VMS) and the maximum principal stress, and compared to the reported FE and strain gauge data. Our qualitative stress analysis indicates that occlusal forces distribute through the mid-facial skeleton along five vertical and two horizontal buttresses. We demonstrated that cortical bone has a priority in the transfer of occlusal load in the anterior maxilla, whereas both cortical and trabecular bone in the posterior maxilla are equally involved in performing this task. Observed site dependence of the occlusal load distribution may help clinicians in creating strategies for implantology and orthodontic treatments. Additionally, the magnitude of VMS in our model was significantly lower in comparison to previous FE models composed only of cortical bone. This finding suggests that both cortical and trabecular bone should be modeled whenever stress will be quantitatively analyzed.

Prediction of coronary plaque location on arteries having myocardial bridge, using finite element models.

This study was performed to evaluate the influences of the myocardial bridges on the plaque initializations and progression in the coronary arteries. The wall structure is changed due to the plaque presence, which could be the reason for multiple heart malfunctions. Using simplified parametric finite element model (FE model) of the coronary artery having myocardial bridge and analyzing different mechanical parameters from blood circulation through the artery (wall shear stress, oscillatory shear index, residence time), we investigated the prediction of "the best" position for plaque progression. We chose six patients from the angiography records and used data from DICOM images to generate FE models with our software tools for FE preprocessing, solving and post-processing. We found a good correlation between real positions of the plaque and the ones that we predicted to develop at the proximal part of the myocardial bridges with wall shear stress, oscillatory shear index and residence time. This computer model could be additional predictive tool for everyday clinical examination of the patient with myocardial bridge.

Microstructural properties of the mid-facial bones in relation to the distribution of occlusal loading.

Although the concept of the occlusal load transfer through the facial skeleton along the buttresses has been extensively studied, there has been no study to link microarchitecture of the mid-facial bones to the occlusal load distribution. The aim of this study was to analyze micro-structural properties of the mid-facial bones in relation to occlusal stress. The study was performed by combining the three-dimensional finite element analysis (3D FEA) and micro-computed tomography analysis (micro-CT). Clenching was simulated on the computer model of the adult male human skull which was also used as a source of bone specimens. After the FEA was run, stress was measured at the specific sites in cortical shell and trabecular bone of the model along and between the buttresses. From the corresponding sites on the skull, twenty-five cortical and thirteen cancellous bone specimens were harvested. The specimens were classified into high stress or low stress group based on the stress levels measured via the FEA. Micro-architecture of each specimen was assessed by micro-CT. In the high stress group, cortical bone showed a tendency toward greater thickness and density, lower porosity, and greater pore separation. Stress-related differences in microstructure between the groups were more pronounced in trabecular bone, which showed significantly greater bone volume fraction (BV/TV) and trabecular thickness (Tb.Th) in the high stress group. Our results suggest that the mid-facial bones in the adult dentate male skull exhibit regional variations in cortical and trabecular bone micro-architecture that could be a consequence of different occlusal stress.

Computational analysis of lung deformation after murine pneumonectomy. [corrected].

In many mammalian species, the removal of one lung (pneumonectomy) is associated with the compensatory growth of the remaining lung. To investigate the hypothesis that parenchymal deformation may trigger lung regeneration, we used microCT scanning to create 3D finite element geometric models of the murine lung pre- and post-pneumonectomy (24 h). The structural correspondence between models was established using anatomic landmarks and an iterative computational algorithm. When compared with the pre-pneumonectomy lung, the post-pneumonectomy models demonstrated significant translation and rotation of the cardiac lobe into the post-pneumonectomy pleural space. 2D maps of lung deformation demonstrated significant heterogeneity; the areas of greatest deformation were present in the subpleural regions of the lobe. Consistent with the previously identified growth patterns, subpleural regions of enhanced deformation are compatible with a mechanical signal - likely involving parenchymal stretch - triggering lung growth.

Computer simulation of cervical tissue response to a hydraulic dilator device.

BACKGROUND: Classical mechanical dilators for cervical dilation are associated with various complications, such as uterine perforation, cervical laceration, infections and intraperitoneal hemorrhage. A new medical device called continuous controllable balloon dilator (CCBD) was constructed to make a significant reduction in all of the side effects of traditional mechanical dilation. METHOD: In this study we investigated numerically the cervical canal tissue response for Hegar and CCBD using our poroelastic finite element model and in-house software development. Boundary conditions for pressure loading on the tissue for both dilators in vivo were measured experimentally. Material properties of the cervical tissue were fitted with experimental in vivo data of pressure and fluid volume or balloon size. RESULTS: Obtained results for effective stresses inside the cervical tissue clearly showed higher stresses for Hegar dilator during dilation in comparison with our CCBD. CONCLUSION: This study opens a new avenue for the implementation of CCBD device instead of mechanical dilators to prevent cervical injury during cervical dilation.

Mapping cyclic stretch in the postpneumonectomy murine lung.

In many mammalian species, the removal of one lung [pneumonectomy (PNX)] is associated with the compensatory growth of the remaining lung. To investigate the hypothesis that parenchymal deformation may trigger lung regeneration, we used respiratory-gated micro-computed tomography scanning to create three-dimensional finite-element geometric models of the murine cardiac lobe with cyclic breathing. Models were constructed of respiratory-gated micro-computed tomography scans pre-PNX and 24 h post-PNX. The computational models demonstrated that the maximum stretch ratio map was patchy and heterogeneous, particularly in subpleural, juxta-diaphragmatic, and cephalad regions of the lobe. In these parenchymal regions, the material line segments at peak inspiration were frequently two- to fourfold greater after PNX; some regions of the post-PNX cardiac lobe demonstrated parenchymal compression at peak inspiration. Similarly, analyses of parenchymal maximum shear strain demonstrated heterogeneous regions of mechanical stress with focal regions demonstrating a threefold increase in shear strain after PNX. Consistent with previously identified growth patterns, these subpleural regions of enhanced stretch and shear strain are compatible with a mechanical signal, likely involving cyclic parenchymal stretch, triggering lung growth.

Computer simulation of thromboexclusion of the complete aorta in the treatment of chronic type B aneurysm.

The purpose of this computational study was to examine the hemodynamic parameters of the velocity fields, shear stress, pressure and drag force field in the complex aorta system, based on a case of type B aortic dissection. The extra-anatomic reconstruction of the complete aorta and bipolar exclusion of the aneurysm was investigated by computational fluid dynamics. Three different cases of the same patient were analyzed: the existing preoperative condition and two alternative surgical treatment options, cases A and B, involving different distal aorto-aortic anastomosis sites. The three-dimensional Navier-Stokes equations and the continuity equation were solved with an unsteady stabilized finite element method. The aorta and large tube graft geometries were reconstructed based on CT angiography images to generate a patient-specific 3D finite element mesh. The computed results showed velocity profiles with smaller intensity in the aorta than in the graft tube in the postoperative case. The shear stress distribution showed low zones around 0.5 Pa in the aneurysm part of the aorta for all three cases. Pressure distribution and, particularly, drag force had much higher values in the preoperative aneurysm zones (7.37 N) than postoperatively (2.45 N), which provides strong evidence of the hemodynamic and biomechanical benefits of this type of intervention in this specific patient. After assessing the outcome obtained with each of the two alternatives A and B, for which we found no significant difference, it was decided to use option A to treat the patient. In summary, computational studies could complement surgical preoperative risk assessment and provide significant insight into the benefits of different treatment alternatives.

Patient-specific prediction of coronary plaque growth from CTA angiography: a multiscale model for plaque formation and progression.

Computational fluid dynamics methods based on in vivo 3-D vessel reconstructions have recently been identified the influence of wall shear stress on endothelial cells as well as on vascular smooth muscle cells, resulting in different events such as flow mediated vasodilatation, atherosclerosis, and vascular remodeling. Development of image-based modeling technologies for simulating patient-specific local blood flows is introducing a novel approach to risk prediction for coronary plaque growth and progression. In this study, we developed 3-D model of plaque formation and progression that was tested in a set of patients who underwent coronary computed tomography angiography (CTA) for anginal symptoms. The 3-D blood flow is described by the Navier-Stokes equations, together with the continuity equation. Mass transfer within the blood lumen and through the arterial wall is coupled with the blood flow and is modeled by a convection-diffusion equation. The low density lipoprotein (LDL) transports in lumen of the vessel and through the vessel tissue (which has a mass consumption term) are coupled by Kedem-Katchalsky equations. The inflammatory process is modeled using three additional reaction-diffusion partial differential equations. A full 3-D model was created. It includes blood flow and LDL concentration, as well as plaque formation and progression. Furthermore, features potentially affecting plaque growth, such as patient risk score, circulating biomarkers, localization and composition of the initial plaque, and coronary vasodilating capability were also investigated. The proof of concept of the model effectiveness was assessed by repetition of CTA, six months after.

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.