Post-angioplasty remodeling of coronary arteries investigated via a chemo-mechano-biological in silico model.

This work presents the application of a chemo-mechano-biological constitutive model of soft tissues for describing tissue inflammatory response to damage in collagen constituents. The material model is implemented into a nonlinear finite element formulation to follow up a coronary standard balloon angioplasty for one year. Numerical results, compared with available in vivo clinical data, show that the model reproduces the temporal dynamics of vessel remodeling associated with subintimal damage. Such dynamics are bimodular, being characterized by an early tissue resorption and lumen enlargement, followed by late tissue growth and vessel constriction. Applicability of the modeling framework in retrospective studies is demonstrated, and future extension towards prospective applications is discussed.

Mechano-chemo-biological model of atherosclerosis formation based on the outside-in theory.

Atherosclerosis is a disease in blood vessels that often results in plaque formation and lumen narrowing. It is an inflammatory response of the tissue caused by disruptions in the vessel wall nourishment. Blood vessels are nourished by nutrients originating from the blood of the lumen. In medium-sized and larger vessels, nutrients are additionally provided from outside through a network of capillaries called vasa vasorum. It has recently been hypothesized (Haverich in Circulation 135:205-207, 2017) that the root of atherosclerotic diseases is the malfunction of the vasa vasorum. This, so-called outside-in theory, is supported by a recently developed numerical model (Soleimani et al. in Arch Comput Methods Eng 28:4263-4282, 2021) accounting for the inflammation initiation in the adventitial layer of the blood vessel. Building on the previous findings, this work proposes an extended material model for atherosclerosis formation that is based on the outside-in theory. Beside the description of growth kinematics and nutrient diffusion, the roles of monocytes, macrophages, foam cells, smooth muscle cells and collagen are accounted for in a nonlinear continuum mechanics framework. Cells are activated due to a lack of vessel wall nourishment and proliferate, migrate, differentiate and synthesize collagen, leading to the formation of a plaque. Numerical studies show that the onset of atherosclerosis can qualitatively be reproduced and back the new theory.

Mathematical modeling and numerical simulation of arterial dissection based on a novel surgeon's view.

This paper presents a mathematical model for arterial dissection based on a novel hypothesis proposed by a surgeon, Axel Haverich, see Haverich (Circulation 135(3):205-207, 2017. https://doi.org/10.1161/circulationaha.116.025407 ). In an attempt and based on clinical observations, he explained how three different arterial diseases, namely atherosclerosis, aneurysm and dissection have the same root in malfunctioning Vasa Vasorums (VVs) which are micro capillaries responsible for artery wall nourishment. The authors already proposed a mathematical framework for the modeling of atherosclerosis which is the thickening of the artery walls due to an inflammatory response to VVs dysfunction. A multiphysics model based on a phase-field approach coupled with mechanical deformation was proposed for this purpose. The kinematics of mechanical deformation was described using finite strain theory. The entire model is three-dimensional and fully based on a macroscopic continuum description. The objective here is to extend that model by incorporating a damage mechanism in order to capture the tearing (rupture) in the artery wall as a result of micro-injuries in VV. Unlike the existing damage-based model of the dissection in the literature, here the damage is driven by the internal bleeding (hematoma) rather than purely mechanical external loading. The numerical implementation is carried out using finite element method (FEM).

Numerical and experimental investigation of multi-species bacterial co-aggregation.

This paper deals with the mathematical modeling of bacterial co-aggregation and its numerical implementation in a FEM framework. Since the concept of co-aggregation refers to the physical binding between cells of different microbial species, a system composed of two species is considered in the modeling framework. The extension of the model to an arbitrary number of species is straightforward. In addition to two-species (multi-species growth) dynamics, the transport of a nutritional substance and the extent of co-aggregation are introduced into the model as the third and fourth primary variables. A phase-field modeling approach is employed to describe the co-aggregation between the two species. The mathematical model is three-dimensional and fully based on the continuum description of the problem without any need for discrete agents which are the key elements of the individual-based modeling approach. It is shown that the use of a phase-field-based model is equivalent to a particular form of classical diffusion-reaction systems. Unlike the so-called mixture models, the evolution of each component of the multi-species system is captured thanks to the inherent capability of phase-field modeling in treating systems consisting of distinct multi-phases. The details of numerical implementation in a FEM framework are also presented. Indeed, a new multi-field user element is developed and implemented in ANSYS for this multiphysics problem. Predictions of the model are compared with the experimental observations. By that, the versatility and applicability of the model and the numerical tool are well established.

Arterial tissues and their inflammatory response to collagen damage: A continuum in silico model coupling nonlinear mechanics, molecular pathways, and cell behavior.

Damage in soft biological tissues causes an inflammatory reaction that initiates a chain of events to repair the tissue. This work presents a continuum model and its in silico implementation that describe the cascade of mechanisms leading to tissue healing, coupling mechanical as well as chemo-biological processes. The mechanics is described by means of a Lagrangian nonlinear continuum mechanics framework and follows the homogenized constrained mixtures theory. Plastic-like damage, growth and remodeling as well as homeostasis are taken into account. The chemo-biological pathways account for two molecular and four cellular species, and are activated by damage of collagen molecules in fibers. To consider proliferation, differentiation, diffusion and chemotaxis of species, diffusion-advection-reaction equations are employed. To the best of authors' knowledge, the proposed model combines for the first time such high number of chemo-mechano-biological mechanisms in a consistent continuum biomechanical framework. The resulting set of coupled differential equations describe balance of linear momentum, evolution of kinematic variables as well as mass balance equations. They are discretized in time according to a backward Euler finite difference scheme, and in space through a finite element Galerkin discretization. The features of the model are firstly demonstrated presenting the species dynamics and highlighting the influence of damage intensities on the growth outcome. In terms of a biaxial test, the chemo-mechano-biological coupling and the model's applicability to reproduce normal as well as pathological healing are shown. A last numerical example underlines the model's applicability to complex loading scenarios and inhomogeneous damage distributions. Concluding, the present work contributes towards comprehensive in silico models in biomechanics and mechanobiology.

Uncertain Dynamic Characteristic Analysis for Structures with Spatially Dependent Random System Parameters.

This work presents a robust non-deterministic free vibration analysis for engineering structures with random field parameters in the frame of stochastic finite element method. For this, considering the randomness and spatial correlation of structural physical parameters, a parameter setting model based on random field theory is proposed to represent the random uncertainty of parameters, and the stochastic dynamic characteristics of different structural systems are then analyzed by incorporating the presented parameter setting model with finite element method. First, Gauss random field theory is used to describe the uncertainty of structural material parameters, the random parameters are then characterized as the standard deviation and correlation length of the random field, and the random field parameters are then discretized with the Karhunen-Loeve expansion method. Moreover, based on the discretized random parameters and finite element method, structural dynamic characteristics analysis is addressed, and the probability distribution density function of the random natural frequency is estimated based on multi-dimensional kernel density estimation method. Finally, the random field parameters of the structures are quantified by using the maximum likelihood estimation method to verify the effectiveness of the proposed method and the applicability of the constructed model. The results indicate that (1) for the perspective of maximum likelihood estimation, the parameter setting at the maximum value point is highly similar to the input parameters; (2) the random field considering more parameters reflects a more realistic structure.

In vivo investigation of open-pored magnesium scaffolds LAE442 with different coatings in an open wedge defect.

The magnesium alloy LAE442 showed promising results as a bone substitute in numerous studies in non-weight bearing bone defects. This study aimed to investigate the in vivo behavior of wedge-shaped open-pored LAE442 scaffolds modified with two different coatings (magnesium fluoride (MgF2, group 1)) or magnesium fluoride/calcium phosphate (MgF2/CaP, group 2)) in a partial weight-bearing rabbit tibia defect model. The implantation of the scaffolds was performed as an open wedge corrective osteotomy in the tibia of 40 rabbits and followed for observation periods of 6, 12, 24, and 36 weeks. Radiological and microcomputed tomographic examinations were performed in vivo. X-ray microscopic, histological, histomorphometric, and SEM/EDS analyses were performed at the end of each time period. µCT measurements and X-ray microscopy showed a slight decrease in volume and density of the scaffolds of both coatings. Histologically, endosteal and periosteal callus formation with good bridging and stabilization of the osteotomy gap and ingrowth of bone into the scaffold was seen. The MgF2 coating favored better bridging of the osteotomy gap and more bone-scaffold contacts, especially at later examination time points. Overall, the scaffolds of both coatings met the requirement to withstand the loads after an open wedge corrective osteotomy of the proximal rabbit tibia. However, in addition to the inhomogeneous degradation behavior of individual scaffolds, an accumulation of gas appeared, so the scaffold material should be revised again regarding size dimension and composition.

Effect of pore size on tissue ingrowth and osteoconductivity in biodegradable Mg alloy scaffolds.

Magnesium has mechanical properties similar to those of bone and is being considered as a potential bone substitute. In the present study, two different pore sized scaffolds of the Mg alloy LAE442, coated with magnesium fluoride, were compared. The scaffolds had interconnecting pores of either 400 (p400) or 500 µm (p500). ß-TCP served as control. Ten scaffolds per time group (6, 12, 24, 36 weeks) were implanted in the trochanter major of rabbits. Histological analyses, µCT scans, and SEM/EDX were performed. The scaffolds showed slow volume decreases (week 36 p400: 9.9%; p500: 7.5%), which were accompanied by uncritical gas releases. In contrast, ß-TCP showed accelerated resorption (78.5%) and significantly more new bone inside (18.19 ± 1.47 mm3). Bone fragments grew into p400 (0.17 ± 0.19 mm3) and p500 (0.36 ± 0.26 mm3), reaching the centrally located pores within p500 more frequently. In particular, p400 displayed a more uneven and progressively larger surface area (week 36 p400: 253.22 ± 19.44; p500: 219.19 ± 4.76 mm2). A better osseointegration of p500 was indicated by significantly more trabecular contacts and a 200 µm wide bone matrix being in the process of mineralization and in permanent contact with the scaffold. The number of macrophages and foreign body giant cells were at an acceptable level concerning resorbable biomaterials. In terms of ingrown bone and integrative properties, LAE442 scaffolds could not achieve the results of ß-TCP. In this long-term study, p500 appears to be a biocompatible and more osteoconductive pore size for the Mg alloy LAE442.

Influence of Moisture Content and Wet Environment on the Fatigue Behaviour of High-Strength Concrete.

The influence of a wet environment on the fatigue behaviour of high-strength concrete has become more important in recent years with the expansion of offshore wind energy systems. According to the few investigations documented in the literature, the fatigue resistance of specimens submerged in water is significantly lower compared to that of specimens in dry conditions. However, it is still not clear how the wet environment and the moisture content in concrete influence its fatigue behaviour and which damage mechanisms are involved in the deterioration process. Here the results of a joint project are reported, in which the impact of moisture content in concrete on fatigue deterioration are investigated experimentally and numerically. Aside from the number of cycles to failure, the development of stiffness and acoustic emission (AE) hits are analysed as damage inductors and discussed along with results of microstructural investigations to provide insights into the degradation mechanisms. Subsequently, an efficient numeric modelling approach to water-induced fatigue damage is presented. The results of the fatigue tests show an accelerated degradation behaviour with increasing moisture content of the concrete. Further, it was found that the AE hits of specimens submerged in water occur exclusively close to the minimum stress level in contrast to specimens subjected to dry conditions, which means that additional damage mechanisms are acting with increasing moisture content in the concrete.

Loading equine oocytes with cryoprotective agents captured with a finite element method model.

Cryopreservation can be used to store equine oocytes for extended periods so that they can be used in artificial reproduction technologies at a desired time point. It requires use of cryoprotective agents (CPAs) to protect the oocytes against freezing injury. The intracellular introduction of CPAs, however, may cause irreversible osmotic damage. The response of cells exposed to CPA solutions is governed by the permeability of the cellular membrane towards water and the CPAs. In this study, a mathematical mass transport model describing the permeation of water and CPAs across an oocyte membrane was used to simulate oocyte volume responses and concomitant intracellular CPA concentrations during the exposure of oocytes to CPA solutions. The results of the analytical simulations were subsequently used to develop a phenomenological finite element method (FEM) continuum model to capture the response of oocytes exposed to CPA solutions with spatial information. FEM simulations were used to depict spatial differences in CPA concentration during CPA permeation, namely at locations near the membrane surface and towards the middle of the cell, and to capture corresponding changes in deformation and hydrostatic pressure. FEM simulations of the multiple processes occurring during CPA loading of oocytes are a valuable tool to increase our understanding of the mechanisms underlying cryopreservation outcome.

Mathematical Modeling and Numerical Simulation of Atherosclerosis Based on a Novel Surgeon's View.

This paper deals with the mathematical modeling of atherosclerosis based on a novel hypothesis proposed by a surgeon, Prof. Dr. Axel Haverich (Circulation 135(3):205-207, 2017). Atherosclerosis is referred as the thickening of the artery walls. Currently, there are two schools of thoughts for explaining the root of such phenomenon: thickening due to substance deposition and thickening as a result of inflammatory overgrowth. The hypothesis favored here is the second paradigm stating that the atherosclerosis is nothing else than the inflammatory response of of the wall tissues as a result of disruption in wall nourishment. It is known that a network of capillaries called vasa vasorum (VV) accounts for the nourishment of the wall in addition to the natural diffusion of nutrient from the blood passing through the lumen. Disruption of nutrient flow to the wall tissues may take place due to the occlusion of vasa vasorums with viruses, bacteria and very fine dust particles such as air pollutants referred to as PM 2.5. They can enter the body through the respiratory system at the first place and then reach the circulatory system. Hence in the new hypothesis, the root of atherosclerotic vessel is perceived as the malfunction of microvessels that nourish the vessel. A large number of clinical observation support this hypothesis. Recently and highly related to this work, and after the COVID-19 pandemic, one of the most prevalent disease in the lungs are attributed to the atherosclerotic pulmonary arteries, see Boyle and Haverich (Eur J Cardio Thorac Surg 58(6):1109-1110, 2020). In this work, a general framework is developed based on a multiphysics mathematical model to capture the wall deformation, nutrient availability and the inflammatory response. For the mechanical response an anisotropic constitutive relation is invoked in order to account for the presence of collagen fibers in the artery wall. A diffusion-reaction equation governs the transport of the nutrient within the wall. The inflammation (overgrowth) is described using a phase-field type equation with a double well potential which captures a sharp interface between two regions of the tissues, namely the healthy and the overgrowing part. The kinematics of the growth is treated by classical multiplicative decomposition of the gradient deformation. The inflammation is represented by means of a phase-field variable. A novel driving mechanism for the phase field is proposed for modeling the progression of the pathology. The model is 3D and fully based on the continuum description of the problem. The numerical implementation is carried out using FEM. Predictions of the model are compared with the clinical observations. The versatility and applicability of the model and the numerical tool allow.

Biomechanical Effects of a Cross Connector in Sacral Fractures - A Finite Element Analysis.

Background: Spinopelvic fractures and approaches of operative stabilization have been a source of controversial discussion. Biomechanical data support the benefit of a spinopelvic stabilization and minimally invasive procedures help to reduce the dissatisfying complication rate. The role of a cross connector within spinopelvic devices remains inconclusive. We aimed to analyze the effect of a cross connector in a finite element model (FE model). Study Design: A FE model of the L1-L5 spine segment with pelvis and a spinopelvic stabilization was reconstructed from patient-specific CT images. The biomechanical relevance of a cross connector in a Denis zone I (AO: 61-B2) sacrum fracture was assessed in the FE model by applying bending and twisting forces with and without a cross connector. Biomechanical outcomes from the numerical model were investigated also considering uncertainties in material properties and levels of osseointegration. Results: The designed FE model showed comparable values in range-of-motion (ROM) and stresses with reference to the literature. The superiority of the spinopelvic stabilization (L5/Os ilium) ± cross connector compared to a non-operative procedure was confirmed in all analyzed loading conditions by reduced ROM and principal stresses in the disk L5/S1, vertebral body L5 and the fracture area. By considering the combination of all loading cases, the presence of a cross connector reduced the maximum stresses in the fracture area of around 10%. This difference has been statistically validated (p < 0.0001). Conclusion: The implementation of a spinopelvic stabilization (L5/Os ilium) in sacrum fractures sustained the fracture and led to enhanced biomechanical properties compared to a non-reductive procedure. While the additional cross connector did not alter the resulting ROM in L4/L5 or L5/sacrum, the reduction of the maximum stresses in the fracture area was significant.

Computational model of damage-induced growth in soft biological tissues considering the mechanobiology of healing.

Healing in soft biological tissues is a chain of events on different time and length scales. This work presents a computational framework to capture and couple important mechanical, chemical and biological aspects of healing. A molecular-level damage in collagen, i.e., the interstrand delamination, is addressed as source of plastic deformation in tissues. This mechanism initiates a biochemical response and starts the chain of healing. In particular, damage is considered to be the stimulus for the production of matrix metalloproteinases and growth factors which in turn, respectively, degrade and produce collagen. Due to collagen turnover, the volume of the tissue changes, which can result either in normal or pathological healing. To capture the mechanisms on continuum scale, the deformation gradient is multiplicatively decomposed in inelastic and elastic deformation gradients. A recently proposed elasto-plastic formulation is, through a biochemical model, coupled with a growth and remodeling description based on homogenized constrained mixtures. After the discussion of the biological species response to the damage stimulus, the framework is implemented in a mixed nonlinear finite element formulation and a biaxial tension and an indentation tests are conducted on a prestretched flat tissue sample. The results illustrate that the model is able to describe the evolutions of growth factors and matrix metalloproteinases following damage and the subsequent growth and remodeling in the respect of equilibrium. The interplay between mechanical and chemo-biological events occurring during healing is captured, proving that the framework is a suitable basis for more detailed simulations of damage-induced tissue response.

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.

A Review on Cementitious Self-Healing and the Potential of Phase-Field Methods for Modeling Crack-Closing and Fracture Recovery.

Improving the durability and sustainability of concrete structures has been driving the enormous number of research papers on self-healing mechanisms that have been published in the past decades. The vast developments of computer science significantly contributed to this and enhanced the various possibilities numerical simulations can offer to predict the entire service life, with emphasis on crack development and cementitious self-healing. The aim of this paper is to review the currently available literature on numerical methods for cementitious self-healing and fracture development using Phase-Field (PF) methods. The PF method is a computational method that has been frequently used for modeling and predicting the evolution of meso- and microstructural morphology of cementitious materials. It uses a set of conservative and non-conservative field variables to describe the phase evolutions. Unlike traditional sharp interface models, these field variables are continuous in the interfacial region, which is typical for PF methods. The present study first summarizes the various principles of self-healing mechanisms for cementitious materials, followed by the application of PF methods for simulating microscopic phase transformations. Then, a review on the various PF approaches for precipitation reaction and fracture mechanisms is reported, where the final section addresses potential key issues that may be considered in future developments of self-healing models. This also includes unified, combined and coupled multi-field models, which allow a comprehensive simulation of self-healing processes in cementitious materials.

Investigation of degraded bone substitutes made of magnesium alloy using scanning electron microscope and nanoindentation.

Degradable bone substitutes made of magnesium alloys are an alternative to biological bone grafts. The main advantage is that they can be manufactured location- and patient-specific. To develop and scale appropriate implants using computational models, knowledge about the mechanical properties and especially the change in the properties during the degradation process is essential. Therefore, degraded open-pored implants were investigated using scanning electron microscope and nanoindentation to find their material composition and mechanical properties. Using both techniques the correlation of the material composition and the average modulus was determined. It could be shown that the average modulus of the degradation layer is distinctly lower than that of the base material. The local average modulus of degrading implant highly depends on the magnesium concentration and the accumulation of elements from the environment. A decrease in magnesium concentration leads to a decrease in the average modulus. Thus, the degrading implant had a lower stiffness than the initial structure.

Comparison of two pore sizes of LAE442 scaffolds and their effect on degradation and osseointegration behavior in the rabbit model.

The magnesium alloy LAE442 emerged as a possible bioresorbable bone substitute over a decade ago. In the present study, using the investment casting process, scaffolds of the Magnesium (Mg) alloy LAE442 with two different and defined pore sizes, which had on average a diameter of 400 µm (p400) and 500 µm (p500), were investigated to evaluate degradation and osseointegration in comparison to a ß-TCP control group. Open-pored scaffolds were implanted in both greater trochanter of rabbits. Ten scaffolds per time group (6, 12, 24, and 36 weeks) and type were analyzed by clinical, radiographic and µ-CT examinations (2D and 3D). None of the scaffolds caused adverse reactions. LAE442 p400 and p500 developed moderate gas accumulation due to the Mg associated in vivo corrosion, which decreased from week 20 for both pore sizes. After 36 weeks, p400 and p500 showed volume decreases of 15.9 and 11.1%, respectively, with homogeneous degradation, whereas ß-TCP lost 74.6% of its initial volume. Compared to p400, osseointegration for p500 was significantly better at week 2 postsurgery due to more frequent bone-scaffold contacts, higher number of trabeculae and higher bone volume in the surrounding area. No further significant differences between the two pore sizes became apparent. However, p500 was close to the values of ß-TCP in terms of bone volume and trabecular number in the scaffold environment, suggesting better osseointegration for the larger pore size.

A simulation model for the degradation of magnesium-based bone implants.

The development of degradable bone implants, in particular made of metal materials, is an emerging field. The advantage of degradable implants is that they do not have to be removed later. In order to be able to develop and scale appropriate implants for different applications, it is necessary to know the change in mechanical properties of the implant during the degradation process in general and at different locations. One area of bone implants are bone substitute materials. They are deployed when there is a defect in the bone which cannot be filled autonomously by the body. In this study, a numerical degradation model of magnesium-based bone substitute materials is developed using the finite element method. Computational models are being developed to reduce experimental animal research in future. Magnesium is a naturally occurring material which is needed to build enzymes in the body. Additionally, magnesium has a Young's modulus close to native bone, wherefore it is attractive for medical applications with bone contact. The simulation model is based on the assumption that the degradation is a diffusion-controlled process driven by the dissolution of magnesium. The model is adapted to a 3D open-pored structure made of the magnesium alloy LAE442. Previous studies showed that implants made of LAE442 lose stiffness without a volume reduction. To simulate the change in mechanical properties, a concentration-dependent Young's modulus is assumed. With this model the formation of the degradation layer is computable as well as the change in mechanical properties, as measured by the effective Young's modulus of the structure. The movement of the interface between the not-degraded and degraded material is modelled using the level set method.

Experimental characterization and computational modeling of hydrogel cross-linking for bioprinting applications.

Alginate-based hydrogels are extensively used to create bioinks for bioprinting, due to their biocompatibility, low toxicity, low costs, and slight gelling. Modeling of bioprinting process can boost experimental design reducing trial-and-error tests. To this aim, the cross-linking kinetics for the chemical gelation of sodium alginate hydrogels via calcium chloride diffusion is analyzed. Experimental measurements on the absorbed volume of calcium chloride in the hydrogel are obtained at different times. Moreover, a reaction-diffusion model is developed, accounting for the dependence of diffusive properties on the gelation degree. The coupled chemical system is solved using finite element discretizations which include the inhomogeneous evolution of hydrogel state in time and space. Experimental results are fitted within the proposed modeling framework, which is thereby calibrated and validated. Moreover, the importance of accounting for cross-linking-dependent diffusive properties is highlighted, showing that, if a constant diffusivity property is employed, the model does not properly capture the experimental evidence. Since the analyzed mechanisms highly affect the evolution of the front of the solidified gel in the final bioprinted structure, the present study is a step towards the development of reliable computational tools for the in silico optimization of protocols and post-printing treatments for bioprinting applications.

Molecular-level collagen damage explains softening and failure of arterial tissues: A quantitative interpretation of CHP data with a novel elasto-damage model.

The present experimental-modelling study provides a quantitative interpretation of mechanical data and damage measurements obtained from collagen hybridizing peptide (CHP) techniques on overstretched sheep cerebral arterial tissues. To this aim, a structurally-motivated constitutive model is developed in the framework of continuum damage mechanics. The model includes two internal variables for describing the effects of collagen triple-helical unfolding via interstrand delamination: one governs plastic mechanisms in collagen fibers, leading to a stress softening response of the tissue at the macroscale; the other one describes the loss of fiber structural integrity, leading to tissue final failure. The proposed model is calibrated using the obtained mechanical experimental data, showing excellent fitting capabilities. The predicted evolution of internal variables agree well with independent measurements of molecular-level CHP-based damage data, obtaining an independent a posteriori validation of damage predictions. Moreover, available data on inelastic tissue elongation following supraphysiological loads are successfully reproduced. These outcomes further the hypothesis that the accumulation of interstrand delamination is a primary cause for the evolution of inelastic mechanisms in tissues, and in particular of stress softening up to failure.