Unraveling the complexity of vascular tone regulation: a multiscale computational approach to integrating chemo-mechano-biological pathways with cardiovascular biomechanics.

Vascular tone regulation is a crucial aspect of cardiovascular physiology, with significant implications for overall cardiovascular health. However, the precise physiological mechanisms governing smooth muscle cell contraction and relaxation remain uncertain. The complexity of vascular tone regulation stems from its multiscale and multifactorial nature, involving global hemodynamics, local flow conditions, tissue mechanics, and biochemical pathways. Bridging this knowledge gap and translating it into clinical practice presents a challenge. In this paper, a computational model is presented to integrate chemo-mechano-biological pathways with cardiovascular biomechanics, aiming to unravel the intricacies of vascular tone regulation. The computational framework combines an algebraic description of global hemodynamics with detailed finite element analyses at the scale of vascular segments for describing their passive and active mechanical response, as well as the molecular transport problem linked with chemo-biological pathways triggered by wall shear stresses. Their coupling is accounted for by considering a two-way interaction. Specifically, the focus is on the role of nitric oxide-related molecular pathways, which play a critical role in modulating smooth muscle contraction and relaxation to maintain vascular tone. The computational framework is employed to examine the interplay between localized alterations in the biomechanical response of a specific vessel segment-such as those induced by calcifications or endothelial dysfunction-and the broader global hemodynamic conditions-both under basal and altered states. The proposed approach aims to advance our understanding of vascular tone regulation and its impact on cardiovascular health. By incorporating chemo-mechano-biological mechanisms into in silico models, this study allows us to investigate cardiovascular responses to multifactorial stimuli and incorporate the role of adaptive homeostasis in computational biomechanics frameworks.

Mechano-chemo-biological Computational Models for Arteries in Health, Disease and Healing: From Tissue Remodelling to Drug-eluting Devices.

This review aims to highlight urgent priorities for the computational biomechanics community in the framework of mechano-chemo-biological models. Recent approaches, promising directions and open challenges on the computational modelling of arterial tissues in health and disease are introduced and investigated, together with in silico approaches for the analysis of drug-eluting stents that promote pharmacological-induced healing. The paper addresses a number of chemo-biological phenomena that are generally neglected in biomechanical engineering models but are most likely instrumental for the onset and the progression of arterial diseases. An interdisciplinary effort is thus encouraged for providing the tools for an effective in silico insight into medical problems. An integrated mechano-chemo-biological perspective is believed to be a fundamental missing piece for crossing the bridge between computational engineering and life sciences, and for bringing computational biomechanics into medical research and clinical practice.

Mechanical performance of Anatomic-Functional-Geometry dental treatments: A computational study.

In this paper the biomechanical response of a novel dental preparation technique, referred to as the Anatomic-Functional-Geometry treatment (AFG), is investigated through a 3D nonlinear finite-element modelling approach. A comparative investigation against a standard technique employed in dental clinical practice is carried out, by simulating typical experimental mechanical tests and physiological functional conditions. Failure mechanisms of treated tooth models are investigated through a progressive damage formulation implemented via a displacement-driven incremental approach. Computational results clearly show that AFG-treated teeth, as a consequence of a more conservative morphological preparation of the tooth, are characterized by more effective crown-dentin loading transfer mechanisms, higher fracture strength levels and more homogeneous stress patterns than the standard-treated ones, thereby opening towards widespread clinical application.

Mechanical behavior of metastatic femurs through patient-specific computational models accounting for bone-metastasis interaction.

This paper proposes a computational model based on a finite-element formulation for describing the mechanical behavior of femurs affected by metastatic lesions. A novel geometric/constitutive description is introduced by modelling healthy bone and metastases via a linearly poroelastic constitutive approach. A Gaussian-shaped graded transition of material properties between healthy and metastatic tissues is prescribed, in order to account for the bone-metastasis interaction. Loading-induced failure processes are simulated by implementing a progressive damage procedure, formulated via a quasi-static displacement-driven incremental approach, and considering both a stress- and a strain-based failure criterion. By addressing a real clinical case, left and right patient-specific femur models are geometrically reconstructed via an ad-hoc imaging procedure and embedding multiple distributions of metastatic lesions along femurs. Significant differences in fracture loads, fracture mechanisms, and damage patterns, are highlighted by comparing the proposed constitutive description with a purely elastic formulation, where the metastasis is treated as a pseudo-healthy tissue or as a void region. Proposed constitutive description allows to capture stress/strain localization mechanisms within the metastatic tissue, revealing the model capability in describing possible strain-induced mechano-biological stimuli driving onset and evolution of the lesion. The proposed approach opens towards the definition of effective computational strategies for supporting clinical decision and treatments regarding metastatic femurs, contributing also to overcome some limitations of actual standards and procedures.

A chemo-mechano-biological formulation for the effects of biochemical alterations on arterial mechanics: the role of molecular transport and multiscale tissue remodelling.

This paper presents a chemo-mechano-biological framework for arterial physiopathology. The model accounts for the fine remodelling in the multiscale hierarchical arrangement of tissue constituents and for the diffusion of molecular species involved in cell-cell signalling pathways. Effects in terms of alterations in arterial compliance are obtained. A simple instructive example is introduced. Although oversimplified with respect to realistic case studies, the proposed application mimics the biochemical activity of matrix metalloproteinases, transforming growth factors beta and interleukins on tissue remodelling. Effects of macrophage infiltration, of intimal thickening and of a healing phase are investigated, highlighting the corresponding influence on arterial compliance. The obtained results show that the present approach is able to capture changes in arterial mechanics as a consequence of the alterations in tissue biochemical environment and cellular activity, as well as to incorporate the protective role of both autoimmune responses and pharmacological treatments.

A FSI computational framework for vascular physiopathology: A novel flow-tissue multiscale strategy.

A novel fluid-structure computational framework for vascular applications is herein presented. It is developed by combining the double multi-scale nature of vascular physiopathology in terms of both tissue properties and blood flow. Addressing arterial tissues, they are modelled via a nonlinear multiscale constitutive rationale, based only on parameters having a clear histological and biochemical meaning. Moreover, blood flow is described by coupling a three-dimensional fluid domain (undergoing physiological inflow conditions) with a zero-dimensional model, which allows to reproduce the influence of the downstream vasculature, furnishing a realistic description of the outflow proximal pressure. The fluid-structure interaction is managed through an explicit time-marching approach, able to accurately describe tissue nonlinearities within each computational step for the fluid problem. A case study associated to a patient-specific aortic abdominal aneurysmatic geometry is numerically investigated, highlighting advantages gained from the proposed multiscale strategy, as well as showing soundness and effectiveness of the established framework for assessing useful clinical quantities and risk indexes.

An integrated computational approach for aortic mechanics including geometric, histological and chemico-physical data.

A novel computational approach for simulating aortic mechanical response is proposed. Patient-specific geometric description is coupled with a multiscale structurally-motivated tissue constitutive model, explicitly accounting for histological, biophysical and biochemical parameters. Accordingly, geometric and constitutive features can be straight included in highly-personalized numerical analyses, allowing to easily incorporate also effects related to possible pathological tissue defects. A parametric home-made code has been developed by integrating an image segmentation technique, a multiscale (nano-to-macro) tissue mechanical description, and a non-linear finite-element strategy. Preliminary numerical results, based on a case study involving a thoracic aortic segment, are presented and discussed, highlighting soundness and effectiveness of the adopted non-linear constitutive modeling. Moreover, the influence on the aortic macroscale response induced by a localized defect affecting the crimp of collagen fibers is analyzed, proving that the proposed multiscale computational framework is able to provide special insights into both etiology of some cardiovascular diseases and physio-pathological remodeling mechanisms.

Analytical modeling of drug dynamics induced by eluting stents in the coronary multi-layered curved domain.

Pharmacokinetics induced by drug eluting stents (DES) in coronary walls is modeled by means of a one-dimensional multi-layered model, accounting for vessel curvature and non-homogeneous properties of the arterial tissues. The model includes diffusion mechanisms, advection effects related to plasma filtration through the walls, and bio-chemical drug reactions. A non-classical Sturm-Liouville problem with discontinuous coefficients is derived, whose closed-form analytical solution is obtained via an eigenfunction expansion. Soundness and consistency of the proposed approach are shown by numerical computations based on possible clinical treatments involving both hydrophilic and hydrophobic drugs. The influence of the main model parameters on drug delivery mechanisms is analyzed, highlighting the effects induced by vessel curvature and yielding comparative indications and useful insights into the concurring mechanisms governing the pharmacokinetics.

Stress and strain localization in stretched collagenous tissues via a multiscale modelling approach.

Mechanobiology of cells in soft collagenous tissues is highly affected by both tissue response at the macroscale and stress/strain localization mechanisms due to features at lower scales. In this paper, the macroscale mechanical behaviour of soft collagenous tissues is modelled by a three-level multiscale approach, based on a multi-step homogenisation technique from nanoscale up to the macroscale. Nanoscale effects, related to both intermolecular cross-links and collagen mechanics, are accounted for, together with geometric nonlinearities at the microscale. Moreover, an effective submodelling procedure is conceived in order to evaluate the local stress and strain fields at the microscale, which is around and within cells. Numerical results, obtained by using an incremental finite element formulation and addressing stretched tendinous tissues, prove consistency and accuracy of the model at both macroscale and microscale, confirming also the effectiveness of the multiscale modelling concept for successfully analysing physiopathological processes in biological tissues.

Comparative evaluation of osseointegrated dental implants based on platform-switching concept: influence of diameter, length, thread shape, and in-bone positioning depth on stress-based performance.

This study aimed to investigate the influence of implant design (in terms of diameter, length, and thread shape), in-bone positioning depth, and bone posthealing crestal morphology on load transfer mechanisms of osseointegrated dental implants based on platform-switching concept. In order to perform an effective multiparametric comparative analysis, 11 implants different in dimensions and in thread features were analyzed by a linearly elastic 3-dimensional finite element approach, under a static load. Implant models were integrated with the detailed model of a maxillary premolar bone segment. Different implant in-bone positioning levels were modeled, considering also different posthealing crestal bone morphologies. Bone overloading risk was quantified by introducing proper local stress measures, highlighting that implant diameter is a more effective design parameter than the implant length, as well as that thread shape and thread details can significantly affect stresses at peri-implant bone, especially for short implants. Numerical simulations revealed that the optimal in-bone positioning depth results from the balance of 2 counteracting effects: cratering phenomena and bone apposition induced by platform-switching configuration. Proposed results contribute to identify the mutual influence of a number of factors affecting the bone-implant loading transfer mechanisms, furnishing useful insights and indications for choosing and/or designing threaded osseointegrated implants.

Implant-bone load transfer mechanisms in complete-arch prostheses supported by four implants: a three-dimensional finite element approach.

STATEMENT OF PROBLEM: Complete-arch restorations supported by fewer than 5 dental implants can induce unbalanced load transfer and tissue overloading, leading to excessive bone resorption and possible clinical failure. This is primarily affected by the cantilever length, the implant design and positioning, and the morphology and properties of the bone. PURPOSE: The purpose of this study was to compare 2 different restorative techniques for complete-arch rehabilitations supported by 4 implants. The primary purpose was to highlight the possible risks of excessive stress and unbalanced load transfer mechanisms and to identify the main biomechanical factors affecting loading transmission. MATERIAL AND METHODS: Three-dimensional (3D) numerical models of edentulous maxillae and mandibles restored with 2 techniques using 4 implants were generated from computed tomography (CT) images and analyzed with linear elastic finite-element simulations with 3 different static loads. The first technique used 2 vertical mesial implants and 2 tilted distal implants (at a 30 degree angle), and the second used vertical implants that fulfilled platform switching concepts. Bone-muscle interactions and temporomandibular joints were included in the mandibular model. Complete implant osseous integration was assumed and different posthealing crestal bone geometries were modeled. Stress measures (revealing risks of tissue overloading) and a performance index (highlighting the main features of the loading partition mechanisms) were introduced and computed to compare the 2 techniques. RESULTS: Dissimilar load transfer mechanisms of the 2 restorative approaches when applied in mandibular and maxillary models were modeled. Prostheses supported by distally tilted implants exhibited a more effective and uniform loading partition than all vertical implants, except in the simulated maxilla under a frontal load. Tilted distal implants reduced compressive states at distal bone-implant interfaces but, depending on bone morphology and loading type, could induce high tensile stresses at distal crests. Overloading risks on mesial periimplant bone decreased when the efficient preservation of the crestal bone through platform switching strategies was modeled. CONCLUSIONS: Numerical simulations highlighted that the cantilever length, the implant design and positioning, and the bone's mechanical properties and morphology can affect both load transmission mechanisms and bone overloading risks in complete-arch restorations supported by 4 implants. Distally tilted implants induced better loading transmission than vertical implants, although the levels of computed stress were physiologically acceptable in both situations.

An insight on multiscale tendon modeling in muscle-tendon integrated behavior.

This paper aims to highlight the need for a refined tendon model to reproduce the main mechanical features of the integrated muscle-tendon unit (MTU). Elastic nonlinearities of the tendon, both at the nano and microscale, are modeled by a multiscale approach, accounting for the hierarchical arrangement (from molecules up to the fibers) of the collagen structures within the tissue. This model accounts also for the variation of tendon stiffness due to physical activity. Since the proposed tendon model is based on tissue-structured histology, the training-driven adaptation laws are directly formulated starting from histological evidences. Such a tendon description is integrated into a viscoelastic Hill-type model of the whole MTU. A fixed-end contraction test is numerically simulated, and results based on both linear and nonlinear tendon elastic model are compared. Sound and effective time-histories of muscle contractile force and fiber length are obtained only accounting for tendon elastic nonlinearities, which allow to quantitatively recover some experimental data. Finally, proposed numerical results give clear indications toward a rational explanation of the influence of tendon remodeling induced by physical activity on muscular contractile force.

Drug release from coronary eluting stents: A multidomain approach.

In this paper, starting from a consistent mathematical model, a novel computational approach is proposed for assessing some biomechanical effects on drug release from coronary drug-eluting stents (DESs), related to tissue properties, local hemodynamics and stent design. A multiscale and multidomain advection-diffusion model is formulated for describing drug dynamics in the polymeric substrate covering the stent, into the arterial wall, and in the vessel lumen. The model accounts for tissue microstructure (anisotropic drug diffusion, porosity, drug retention induced by resident proteins), macrostructure (plaque between stent and tissue), and local hemodynamics. In the case of hydrophobic taxus-based compounds, several numerical analyses have been carried out on simplified geometries by using finite element simulations, performing significant comparisons with other recent studies and highlighting general conclusions for assessing effectiveness of some modelling features as well as useful hints for optimizing drug delivery design and technology.

A unified multiscale mechanical model for soft collagenous tissues with regular fiber arrangement.

In this paper the mechanical response of soft collagenous tissues with regular fiber arrangement (RSCTs) is described by means of a nanoscale model and a two-step micro-macro homogenization technique. The non-linear collagen constitutive behavior is modeled at the nanoscale by a novel approach accounting for entropic mechanisms as well as stretching effects occurring in collagen molecules. Crimped fibers are reduced to equivalent straight ones at the microscale and the constitutive response of RSCTs at the macroscale is formulated by homogenizing a fiber reinforced material. This approach has been applied to different RSCTs (tendon, periodontal ligament and aortic media), resulting effective and accurate as proved by the excellent agreement with available experimental data. The model is based on few parameters, directly related to histological and morphological evidences and whose sensitivity has been widely investigated. Applications to simulation of some physiopathological mechanisms are also proposed, providing confirmation of clinical evidences and quantitative indications helpful for clinical practice.

Optimal mechanical design of anatomical post-systems for endodontic restoration.

This paper analyses the mechanical behaviour of a new reinforced anatomical post-systems (RAPS) for endodontic restoration. The composite restorative material (CRM) completely fills the root canal (as do the commonly used cast metal posts) and multiple prefabricated composite posts (PCPs) are employed as reinforcements. Numerical simulations based on 3D linearly elastic finite element models under parafunctional loads were performed in order to investigate the influence of the stiffness of the CRM and of the number of PCPs. Periodontal ligament effects were taken into account using a discretised anisotropic nonlinearly elastic spring system, and the full discrete model was validated by comparing the resulting stress fields with those obtained with conventional restorations (cast gold-alloy post, homogeneous anatomical post and cemented single PCP) and with the natural tooth. Analysis of the results shows that stresses at the cervical/middle region decrease as CRM stiffness increases and, for large and irregular root cavities that apical stress peaks disappear when multiple PCPs are used. Accordingly, from a mechanical point of view, an optimal RAPS will use multiple PCPs when CRM stiffness is equal to or at most twice that of the dentin. This restorative solution minimises stress differences with respect to the natural tooth, mechanical inhomogeneities, stress concentrations on healthy tissues, volumes subject to shrinkage phenomena, fatigue effects and risks of both root fracture and adhesive/cohesive interfacial failure.

The influence of implant diameter and length on stress distribution of osseointegrated implants related to crestal bone geometry: a three-dimensional finite element analysis.

STATEMENT OF PROBLEM: Load transfer mechanisms and possible failure of osseointegrated implants are affected by implant shape, geometrical and mechanical properties of the site of placement, as well as crestal bone resorption. Suitable estimation of such effects allows for correct design of implant features. PURPOSE: The purpose of this study was to analyze the influence of implant diameter and length on stress distribution and to analyze overload risk of clinically evidenced crestal bone loss at the implant neck in mandibular and maxillary molar periimplant regions. MATERIAL AND METHODS: Stress-based performances of 5 commercially available implants (2 ITI, 2 Nobel Biocare, and 1 Ankylos implant; diameters of 3.3 mm to 4.5 mm, bone-implant interface lengths of 7.5 mm to 12 mm) were analyzed by linearly elastic 3-dimensional finite element simulations, under a static load (lateral component: 100 N; vertical intrusive component: 250 N). Numerical models of maxillary and mandibular molar bone segments were generated from computed tomography images, and local stress measures were introduced to allow for the assessment of bone overload risk. Different crestal bone geometries were also modelled. Type II bone quality was approximated, and complete osseous integration was assumed. RESULTS: Maximum stress areas were numerically located at the implant neck, and possible overloading could occur in compression in compact bone (due to lateral components of the occlusal load) and in tension at the interface between cortical and trabecular bone (due to vertical intrusive loading components). Stress values and concentration areas decreased for cortical bone when implant diameter increased, whereas more effective stress distributions for cancellous bone were experienced with increasing implant length. For implants with comparable diameter and length, compressive stress values at cortical bone were reduced when low crestal bone loss was considered. Finally, dissimilar stress-based performances were exhibited for mandibular and maxillary placements, resulting in higher compressive stress in maxillary situations. CONCLUSIONS: Implant designs, crestal bone geometry, and site of placement affect load transmission mechanisms. Due to the low crestal bone resorption documented by clinical evidence, the Ankylos implant based on the platform switching concept and subcrestal positioning demonstrated better stress-based performance and lower risk of bone overload than the other implant systems evaluated.

Mechanical behaviour of endodontic restorations with multiple prefabricated posts: a finite-element approach.

This paper investigates some mechanical aspects of a new endodontic restoration technique, based on the idea that the root cavity can be more efficiently filled if multiple prefabricated composite posts (PCP) are employed. Multi-post technique increases bearing capacity and durability of endodontically treated teeth, as shown by numerical simulations performed through three-dimensional elastic finite-element static analyses of a lower premolar, constrained by a non-linearly elastic spring system representing the periodontal ligament, under several parafunctional loads. The influence of PCPs' number, material and dimensions is investigated by comparison of the resulting stress fields with those obtained in cases of traditional restorations (cast metal post and cemented single-PCP) and natural tooth, highlighting the advantages of the proposed technique when standard restorative materials are considered. A risk-analysis of root-fracture and interface-failure shows that cast gold-alloy post produces high stress concentrations at post-dentin interface, whereas multi-post solution leads to a behaviour closer to the natural tooth's, exhibiting some advantages with respect to single-PCP restorations. As a matter of fact, whenever PCPs' overall cross-section area increases, multi-post solution induces a significant reduction of stress levels into the residual dentin (and therefore the root-fracture-risk decreases) as well as of the expected polymerization shrinkage effects. Moreover, interfacial stress values in multi-post restorations can be higher than the single-PCP ones when carbon-fibre posts are considered. Nevertheless, the interfacial adhesive/cohesive failure-risk is certainly acceptable if glass-fibre posts are employed.