Experimental validation of auxetic stent designs: three-point bending of 3D printed Titanium prototypes.

Introduction: Numerical simulations have demonstrated the superior bending flexibility of auxetic stents compared to conventional stent designs for endovascular procedures. However, conventional stent manufacturing techniques struggle to produce complex auxetic stent designs, fueling the adoption of additive manufacturing techniques. Methods: In this study, we employed DMLS additive manufacturing to create Titanium Ti64 alloy stent prototypes based on auxetic stent designs investigated in a previous study. These prototypes were then subjected to experimental three-point bending tests. Result: The experimental results were replicated using a finite element model, which showed remarkable accuracy in predicting the bending flexibility of four auxetic stents and two conventional stents. Discussion: Although this validation study demonstrates the promising potential of DMLS and other additive manufacturing methods for fabricating auxetic stents, further optimization of current stent design limitations and the incorporation of post-processing techniques are essential to enhance the reliability of these additive manufacturing processes.

A data-driven computational methodology towards a pre-hospital Acute Ischaemic Stroke screening tool using haemodynamics waveforms.

BACKGROUND AND OBJECTIVE: Acute Ischaemic Stroke (AIS), a significant global health concern, results from occlusions in cerebral arteries, causing irreversible brain damage. Different type of treatments exist depending on the size and location of the occlusion. Challenges persist in achieving faster diagnosis and treatment, which needs to happen in the first hours after the onset of symptoms to maximize the chances of patient recovery. The current diagnostic pipeline, i.e. "drip and ship", involves diagnostic via advanced imaging tools, only available in large clinical facilities, which poses important delays. This study investigates the feasibility of developing a machine learning model to diagnose and locate occluding blood clots from velocity waveforms, which can be easily be obtained with portable devices such as Doppler Ultrasound. The goal is to explore this approach as a cost-effective and time-efficient alternative to advanced imaging techniques typically available only in large hospitals. METHODS: Simulated haemodynamic data is used to conduct blood flow simulations representing healthy and different AIS scenarios using a population-based database. A Machine Learning classification model is trained to solve the inverse problem, this is, detect and locate a potentially occluding thrombus from measured waveforms. The classification process involves two steps. First, the region where the thrombus is located is classified into nine groups, including healthy, left or right large vessel occlusion, left or right anterior cerebral artery, and left or right posterior cerebral artery. In a second step, the bifurcation generation of the thrombus location is classified as small, medium, or large vessel occlusion. RESULTS: The proposed methodology is evaluated for data without noise, achieving a true prediction rate exceeding 95% for both classification steps mentioned above. The inclusion of up to 20% noise reduces the true prediction rate to 80% for region detection and 70% for bifurcation generation detection. CONCLUSIONS: This study demonstrates the potential effectiveness and efficiency of using haemodynamic data and machine learning to detect and locate occluding thrombi in AIS patients. Although the geometric and topological data used in this study are idealized, the results suggest that this approach could be applicable in real-world situations with appropriate adjustments. Source code is available in https://github.com/ahmetsenemse/Acute-Ischaemic-Stroke-screening-tool-.

Computational Comparison of the Mechanical Behavior of Aortic Stent-Grafts Derived from Auxetic Unit Cells.

PURPOSE: Inappropriate stent-graft (SG) flexibility has been frequently associated with endovascular aortic repair (EVAR) complications such as endoleaks, kinks, and SG migration, especially in tortuous arteries. Stents derived from auxetic unit cells have shown some potential to address these issues as they offer an optimum trade-off between radial stiffness and bending flexibility. METHODS: In this study, we utilized an established finite element (FE)-based approach to replicate the mechanical response of a SG iliac limb derived from auxetic unit cells in a virtual tortuous iliac aneurysm using a combination of a 180° U-bend and intraluminal pressurization. This study aimed to compare the mechanical performance (flexibility and durability) of SG limbs derived from auxetic unit cells and two commercial SG limbs (Z-stented SG and circular-stented SG models) in a virtual tortuous iliac aneurysm. Maximal graft strain and maximum stress in stents were employed as criteria to estimate the durability of SGs, whereas the maximal luminal reduction rate and the bending stiffness were used to assess the flexibility of the SGs. RESULTS: SG limbs derived from auxetic unit cells demonstrated low luminal reduction (range 4-12%) with no kink, in contrast to Z-stented SG, which had a kink in its central area alongside a high luminal reduction (44%). CONCLUSIONS: SG limbs derived from auxetic unit cells show great promise for EVAR applications even at high angulations such as 180°, with acceptable levels of durability and flexibility.

Cell nucleus elastography with the adjoint-based inverse solver.

BACKGROUND AND OBJECTIVES: The mechanics of the nucleus depends on cellular structures and architecture, and impact a number of diseases. Nuclear mechanics is yet rather complex due to heterogeneous distribution of dense heterochromatin and loose euchromatin domains, giving rise to spatially variable stiffness properties. METHODS: In this study, we propose to use the adjoint-based inverse solver to identify for the first time the nonhomogeneous elastic property distribution of the nucleus. Inputs of the inverse solver are deformation fields measured with microscopic imaging in contracting cardiomyocytes. RESULTS: The feasibility of the proposed method is first demonstrated using simulated data. Results indicate accurate identification of the assumed heterochromatin region, with a maximum relative error of less than 5%. We also investigate the influence of unknown Poisson's ratio on the reconstruction and find that variations of the Poisson's ratio in the range [0.3-0.5] result in uncertainties of less than 15% in the identified stiffness. Finally, we apply the inverse solver on actual deformation fields acquired within the nuclei of two cardiomyocytes. The obtained results are in good agreement with the density maps obtained from microscopy images. CONCLUSIONS: Overall, the proposed approach shows great potential for nuclear elastography, with promising value for emerging fields of mechanobiology and mechanogenetics.

Intervertebral Disc Elastography to Relate Shear Modulus and Relaxometry in Compression and Bending.

Intervertebral disc degeneration is the most recognized cause of low back pain, characterized by the decline of tissue structure and mechanics. Image-based mechanical parameters (e.g., strain, stiffness) may provide an ideal assessment of disc function that is lost with degeneration but unfortunately remains underdeveloped. Moreover, it is unknown whether strain or stiffness of the disc may be predicted by MRI relaxometry (e.g. T1 or T2), an increasingly accepted quantitative measure of disc structure. In this study, we quantified T1 and T2 relaxation times and in-plane strains using displacement-encoded MRI within the disc under physiological levels of compression and bending. We then estimated shear modulus in orthogonal image planes and compared these values to relaxation times and strains within regions of the disc. Intratissue strain depended on the loading mode, and shear modulus in the nucleus pulposus was typically an order of magnitude lower than the annulus fibrosis, except in bending, where the apparent stiffness depended on the loading. Relative shear moduli estimated from strain data derived under compression generally did not correspond with those from bending experiments, with no correlations in the sagittal plane and only 4 of 15 regions correlated in the coronal plane, suggesting that future inverse models should incorporate multiple loading conditions. Strain imaging and strain-based estimation of material properties may serve as imaging biomarkers to distinguish healthy and diseased discs. Additionally, image-based elastography and relaxometry may be viewed as complementary measures of disc structure and function to assess degeneration in longitudinal studies.

Fabrication of deformable patient-specific AAA models by material casting techniques.

Background: Abdominal Aortic Aneurysm (AAA) is a balloon-like dilatation that can be life-threatening if not treated. Fabricating patient-specific AAA models can be beneficial for in-vitro investigations of hemodynamics, as well as for pre-surgical planning and training, testing the effectiveness of different interventions, or developing new surgical procedures. The current direct additive manufacturing techniques cannot simultaneously ensure the flexibility and transparency of models required by some applications. Therefore, casting techniques are presented to overcome these limitations and make the manufactured models suitable for in-vitro hemodynamic investigations, such as particle image velocimetry (PIV) measurements or medical imaging. Methods: Two complex patient-specific AAA geometries were considered, and the related 3D models were fabricated through material casting. In particular, two casting approaches, i.e. lost molds and lost core casting, were investigated and tested to manufacture the deformable AAA models. The manufactured models were acquired by magnetic resonance, computed tomography (CT), ultrasound imaging, and PIV. In particular, CT scans were segmented to generate a volumetric reconstruction for each manufactured model that was compared to a reference model to assess the accuracy of the manufacturing process. Results: Both lost molds and lost core casting techniques were successful in the manufacturing of the models. The lost molds casting allowed a high-level surface finish in the final 3D model. In this first case, the average signed distance between the manufactured model and the reference was (-0.2±0.2) mm. However, this approach was more expensive and time-consuming. On the other hand, the lost core casting was more affordable and allowed the reuse of the external molds to fabricate multiple copies of the same AAA model. In this second case, the average signed distance between the manufactured model and the reference was (0.1±0.6) mm. However, the final model's surface finish quality was poorer compared to the model obtained by lost molds casting as the sealing of the outer molds was not as firm as the other casting technique. Conclusions: Both lost molds and lost core casting techniques can be used for manufacturing patient-specific deformable AAA models suitable for hemodynamic investigations, including medical imaging and PIV.

Effect of foot stato-dynamic disorders on hemodynamics of the lower limb using strain-gauge plethysmography.

BACKGROUND: The plantar venous pump (PVP), composed of deep plantar veins, is the most distal contributor to venous return from the lower limbs. A pressing need still exists to assess how plantar muscle contraction and gait affect PVP function, how foot stato-dynamic disorders (FSDs) can contribute to venous insufficiency, and how venous return can be optimally stimulated. Our first objective is to compare the venous blood hemodynamics in lower limbs between healthy subjects with a FSD and healthy subjects without a FSD to understand the influence of foot morphology in the performance of the PVP. Our second objective is to evaluate whether PVP function varies with different plantar pressures. METHODS: A total of 52 healthy volunteers (26 feet with a normal arch as the control group and 26 feet with dysmorphism [13 flat feet and 13 hollow feet]) were included. Strain-gauge plethysmography was performed 8 cm above the medial malleolus at different conditions of PVP stimulation: (1) toe flexion, (2) intermittent pneumatic compression (IPC) with and without an insole, and (3) 3-km/h speed walking on a treadmill barefoot, with shoes, and with shoes and insoles. From the strain-gauge plethysmography, we measured the venous blood ejection fraction (EF). From the pressure sensor placed at the midfoot on the plantar arch during IPC, we obtained the maximal pressure (N/cm2). RESULTS: Toe flexion allowed for ejection of an average of 20% of the total venous volume in both groups. IPC and gait generated a mean EF superior to 100% of the available venous volume. The maximal pressure applied at the midfoot during IPC was lower than the pressure set. No significant differences in the EF or maximal pressure were observed between the two groups. The mean EF was not significantly affected for the pronator and supinator walkers compared with those with normal walking dynamics. Wearing shoes did not significantly affect the mean EF. However, wearing insoles during gait significantly increased the venous return in feet with plantar dysmorphism. CONCLUSIONS: To the best of our knowledge, this clinical study is the first to assess the PVP function in 52 healthy volunteers with and without FSDs. We found that wearing shoes did not significantly affect PVP efficiency but that wearing morphologically adapted insoles significantly improved the venous return in the dysmorphic feet. In our sample of healthy volunteers, the differences observed between the control group and feet with FSDs were not statistically significant.

Stiffness sensing by smooth muscle cells: Continuum mechanics modeling of the acto-myosin role.

Aortic smooth muscle cells (SMCs) play a vital role in maintaining homeostasis in the aorta by sensing and responding to mechanical stimuli. However, the mechanisms that underlie the ability of SMCs to sense and respond to stiffness change in their environment are still partially unclear. In this study, we focus on the role of acto-myosin contractility in stiffness sensing and introduce a novel continuum mechanics approach based on the principles of thermal strains. Each stress fiber satisfies a universal stress-strain relationship driven by a Young's modulus, a contraction coefficient scaling the fictitious thermal strain, a maximum contraction stress and a softening parameter describing the sliding effects between actin and myosin filaments. To account for the inherent variability of cellular responses, large populations of SMCs are modeled with the finite-element method, each cell having a random number and a random arrangement of stress fibers. Moreover, the level of myosin activation in each stress fiber satisfies a Weibull probability density function. Model predictions are compared to traction force measurements on different SMC lineages. It is demonstrated that the model not only predicts well the effects of substrate stiffness on cellular traction, but it can also successfully approximate the statistical variations of cellular tractions induced by intercellular variability. Finally, stresses in the nuclear envelope and in the nucleus are computed with the model, showing that the variations of cytoskeletal forces induced by substrate stiffness directly induce deformations of the nucleus which can potentially alter gene expression. The predictability of the model combined to its relative simplicity are promising assets for further investigation of stiffness sensing in 3D environments. Eventually, this could contribute to decipher the effects of mechanosensitivity impairment, which are known to be at the root of aortic aneurysms.

Non-destructive Characterization of Skeletal Muscle Extracellular Matrix Morphology by Combining Optical Coherence Tomography (OCT) Imaging with Tissue Clearing.

Histology is an essential step to visualize and analyze the microstructure of any biological tissue; however, histological processing is often irreversible, and histological samples are unable to be imaged or tested further. In this work, a novel non-destructive protocol is proposed for morphological analysis of skeletal muscles, combining Optical Coherence Tomography (OCT) imaging with Tissue Clearing. Imaging combining OCT and Propylene Glycol (PG) as a tissue-clearing agent, was performed on rat tail and extensor digitorum longus (EDL) muscle. The results show that the extracellular matrix morphology of skeletal muscles, including muscular fibers and the whole microstructure architecture were clearly identified. PG improved OCT imaging as measured by image quality metric Contrast Per Pixel CPP (increases by 3.9%), Naturalness Image Quality Evaluator NIQE (decreases by 23%), and Volume of Interest VOI size (higher for CPP and lower for NIQE values). The tendon microstructure was observed with less precision, as collagen fibers could not be clearly detected. The reversibility of the optical effects of the PG on the immersed tissue (in a Phosphate-Buffered Saline solution) was studied comparing native and rehydrated OCT image acquisition from a single EDL sample. Optical properties and microstructure visibility (CPP and NIQE) have been recovered to 99% of the native sample values. Moreover, clearing process caused shrinkage of the tissue recovered to 86% of the original width. Future work will aim to employ the proposed experimental protocol to identify the local mechanical properties of biological tissues.

Fast strain mapping in abdominal aortic aneurysm wall reveals heterogeneous patterns.

Abdominal aortic aneurysm patients are regularly monitored to assess aneurysm development and risk of rupture. A preventive surgical procedure is recommended when the maximum aortic antero-posterior diameter, periodically assessed on two-dimensional abdominal ultrasound scans, reaches 5.5 mm. Although the maximum diameter criterion has limited ability to predict aneurysm rupture, no clinically relevant tool that could complement the current guidelines has emerged so far. In vivo cyclic strains in the aneurysm wall are related to the wall response to blood pressure pulse, and therefore, they can be linked to wall mechanical properties, which in turn contribute to determining the risk of rupture. This work aimed to enable biomechanical estimations in the aneurysm wall by providing a fast and semi-automatic method to post-process dynamic clinical ultrasound sequences and by mapping the cross-sectional strains on the B-mode image. Specifically, the Sparse Demons algorithm was employed to track the wall motion throughout multiple cardiac cycles. Then, the cyclic strains were mapped by means of radial basis function interpolation and differentiation. We applied our method to two-dimensional sequences from eight patients. The automatic part of the analysis took under 1.5 min per cardiac cycle. The tracking method was validated against simulated ultrasound sequences, and a maximum root mean square error of 0.22 mm was found. The strain was calculated both with our method and with the established finite-element method, and a very good agreement was found, with mean differences of one order of magnitude smaller than the image spatial resolution. Most patients exhibited a strain pattern that suggests interaction with the spine. To conclude, our method is a promising tool for investigating abdominal aortic aneurysm wall biomechanics as it can provide a fast and accurate measurement of the cyclic wall strains from clinical ultrasound sequences.

Effect of dysmorphic plantar arch on venous hemodynamics of the lower limb.

BACKGROUND: The role of the plantar venous pump (PVP) on venous return is evident but the effects of the foot morphology have never been characterized properly. METHOD: 52 healthy volunteers-26 with normal plantar arch (control) and 26 with dysmorphic plantar arch (in two subgroups: 13 flat feet, 13 hollow feet)-were included. Using Doppler ultrasound, we measured the diameter and the peak systolic velocity in the large veins of the lower limb after PVP stimulation by manual compression and bodyweight transfer. RESULT: The mean peak systolic velocity of the studied veins varied from 12.2 cm/s to 41.7 cm/s in the control group and from 10.9 cm/s to 39.1 cm/s in the dysmorphic plantar group. The foot arch morphology did not affect significantly the venous blood flows, except in the great saphenous vein during manual compression. CONCLUSION: The plantar morphology did not induce a significant increase of venous blood velocity resulting from PVP stimulation.

Machine learning and reduced order modelling for the simulation of braided stent deployment.

Endoluminal reconstruction using flow diverters represents a novel paradigm for the minimally invasive treatment of intracranial aneurysms. The configuration assumed by these very dense braided stents once deployed within the parent vessel is not easily predictable and medical volumetric images alone may be insufficient to plan the treatment satisfactorily. Therefore, here we propose a fast and accurate machine learning and reduced order modelling framework, based on finite element simulations, to assist practitioners in the planning and interventional stages. It consists of a first classification step to determine a priori whether a simulation will be successful (good conformity between stent and vessel) or not from a clinical perspective, followed by a regression step that provides an approximated solution of the deployed stent configuration. The latter is achieved using a non-intrusive reduced order modelling scheme that combines the proper orthogonal decomposition algorithm and Gaussian process regression. The workflow was validated on an idealized intracranial artery with a saccular aneurysm and the effect of six geometrical and surgical parameters on the outcome of stent deployment was studied. We trained six machine learning models on a dataset of varying size and obtained classifiers with up to 95% accuracy in predicting the deployment outcome. The support vector machine model outperformed the others when considering a small dataset of 50 training cases, with an accuracy of 93% and a specificity of 97%. On the other hand, real-time predictions of the stent deployed configuration were achieved with an average validation error between predicted and high-fidelity results never greater than the spatial resolution of 3D rotational angiography, the imaging technique with the best spatial resolution (0.15 mm). Such accurate predictions can be reached even with a small database of 47 simulations: by increasing the training simulations to 147, the average prediction error is reduced to 0.07 mm. These results are promising as they demonstrate the ability of these techniques to achieve simulations within a few milliseconds while retaining the mechanical realism and predictability of the stent deployed configuration.

Patient-specific computational simulations of wound healing following midline laparotomy closure.

In the current study, we developed a new computational methodology to simulate wound healing in soft tissues. We assumed that the injured tissue recovers partially its mechanical strength and stiffness by gradually increasing the volume fraction of collagen fibers. Following the principles of the constrained mixture theory, we assumed that new collagen fibers are deposited at homeostatic tension while the already existing tissue undergoes a permanent deformation due to the effects of remodeling. The model was implemented in the finite-element software Abaqus® through a VUMAT subroutine and applied to a complex and realistic case: simulating wound healing following midline laparotomy closure. The incidence of incisional hernia is still quite significant clinically, and our goal was to investigate different conditions hampering the success of these procedures. We simulated wound healing over periods of 6 months on a patient-specific geometry. One of the outcomes of the finite-element simulations was the width of the wound tissue, which was found to be clinically correlated with the development of incisional hernia after midline laparotomy closure. We studied the impact of different suturing modalities and the effects of situations inducing increased intra-abdominal pressure or its intermittent variations such as coughing. Eventually, the results showed that the main risks of developing an incisional hernia mostly depend on the elastic strains reached in the wound tissue after degradation of the suturing wires. Despite the need for clinical validation, these results are promising for establishing a digital twin of wound healing in midline laparotomy incision.

Patient-Specific Numerical Simulations of Endovascular Procedures in Complex Aortic Pathologies: Review and Clinical Perspectives.

The endovascular technique is used in the first line treatment in many complex aortic pathologies. Its clinical outcome is mostly determined by the appropriate selection of a stent-graft for a specific patient and the operator's experience. New tools are still needed to assist practitioners with decision making before and during procedures. For this purpose, numerical simulation enables the digital reproduction of an endovascular intervention with various degrees of accuracy. In this review, we introduce the basic principles and discuss the current literature regarding the use of numerical simulation for endovascular management of complex aortic diseases. Further, we give the future direction of everyday clinical applications, showing that numerical simulation is about to revolutionize how we plan and carry out endovascular interventions.

Potential of auxetic designs in endovascular aortic repair: A computational study of their mechanical performance.

With the rising popularity of endovascular aortic repair (EVAR) for aortic aneurysms and dissections, there is a crucial need for investigating the delayed appearance of post-EVAR complications such as stent-graft kinking, fracture and migration respectively. These complications have been noted to be influenced by the radial stiffness and bending flexibility attributes of stent-grafts. Auxetic designs with negative Poisson's ratio offer interesting advantages such as enhanced fracture toughness, superior indentation resistance and adaptive stiffness in response to intricate morphology for stenting applications over conventional stent designs. The objective of this study is to propose different auxetic stent candidates and to compare their mechanical performance with two conventional stent candidates for endovascular applications using numerical simulation through crimp/crushing tests for their radial stiffness and three-point bending/kinking tests for their flexibility, respectively. The results demonstrate that the novel hybrid auxetic designs (CRE and CSTAR) possess the best trade-off between radial stiffness and bending flexibility characteristics among all candidates for stent-graft applications.

Computational modeling of multiple myeloma interactions with resident bone marrow cells.

The interaction of multiple myeloma with bone marrow resident cells plays a key role in tumor progression and the development of drug resistance. The tumor cell response involves contact-mediated and paracrine interactions. The heterogeneity of myeloma cells and bone marrow cells makes it difficult to reproduce this environment in in-vitro experiments. The use of in-silico established tools can help to understand these complex problems. In this article, we present a computational model based on the finite element method to define the interactions of multiple myeloma cells with resident bone marrow cells. This model includes cell migration, which is controlled by stress-strain equilibrium, and cell processes such as proliferation, differentiation, and apoptosis. A series of computational experiments were performed to validate the proposed model. Cell proliferation by the growth factor IGF-1 is studied for different concentrations ranging from 0-10 ng/mL. Cell motility is studied for different concentrations of VEGF and fibronectin in the range of 0-100 ng/mL. Finally, cells were simulated under a combination of IGF-1 and VEGF stimuli whose concentrations are considered to be dependent on the cancer-associated fibroblasts in the extracellular matrix. Results show a good agreement with previous in-vitro results. Multiple myeloma growth and migration are shown to correlate linearly to the IGF-1 stimuli. These stimuli are coupled with the mechanical environment, which also improves cell growth. Moreover, cell migration depends on the fiber and VEGF concentration in the extracellular matrix. Finally, our computational model shows myeloma cells trigger mesenchymal stem cells to differentiate into cancer-associated fibroblasts, in a dose-dependent manner.

Hyperelastic and damage properties of the hypoxic aorta treated with Cinaciguat.

Chronic hypoxia during gestation and postnatal period induces pulmonary hypertension, aorta stiffening and vascular remodeling. In this study, we hypothesized that a postnatal treatment with Cinaciguat, a guanylate cyclase activator, may improve the vascular function by enhancing NO-sGC pathways that induce vasodilation. To assess this, we collected aortas from six lambs gestated, born and raised at 3600 masl. Half of these lambs received a Cinaciguat postnatal treatment, while the other half was used as control (vehicle). Uniaxial tension was applied on samples of each group of aortas (control and Cinaciguat-treated) through cyclic loading. The obtained stress-stretch curves were used to identify constitutive parameters of a hyperelastic damage model. These material constants allowed us to assess the softening/dissipation behavior and to characterize the treatment effects. Results showed that Cinaciguat has an effect on the damage behavior at large strains, altering the damage onset under uniaxial tension. We conclude that Cinaciguat, as a vasodilator, can prevent the very early effects of vascular remodeling caused by perinatal hypoxia, and improve the aortic-tissue damage properties of hypoxic lambs.