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Definition of axonal injury tolerances across scales: A computational multiscale approach
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Neuronic Engineering.ORCID iD: 0000-0001-6306-507x
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic brain injury (TBI) is today regarded as a global health challenge. Revealing how external mechanical loads translate into tissue and cellular damage is necessary, not only for the development of better preventive measures, but also for the definition of treatments that could spare the patients from suffering TBI's devastating consequences. Significant advancements have been made in the past decades in the understanding of the biomechanical basis of TBI. Finite element (FE) head models, among others, have proved valuable in clarifying the relation between head kinematic and brain deformations patterns. Nevertheless, a comprehensive picture of TBI pathophysiology across the multiple length scales involved is still lacking.

In this thesis, the multiscale nature of TBI was explicitly considered with the aim of, first, ruling out a mechanically plausible axonal injury mechanism and, second, of defining axonal injury tolerances at different scales. To do so, in Study I, a composite FE model of the axon was developed. The vulnerability of its components was tested in a typical injury scenario. The large and nonhomogeneous deformations observed in the axonal membrane motivated Study II, where the FE axonal model was used in cascade with a molecular model of the axonal plasma membrane (or lipid bilayer). It is at this level --the molecular one-- that mechanoporation can be observed and thresholds can be established in dependence of axonal strain and strain rate.

In Study III, potential mechanistic differences in thresholds derived with single-cell or tissue injury models were investigated. The axon FE model was here expanded in a tissue-like model, where the axon is not only surrounded by matrix, but also by other axons using PBCs. The previously derived molecular-level thresholds were used as a benchmark and tissue-injury models were found to have higher tolerances than single-cell models. In Study IV an experimental approach was adopted to characterize the mechanical behavior of glial tissue (derived from the squid giant axon) at large strains and dynamic rate.

Finally, in Study V, a framework for the multiscale analysis of concussive impacts was proposed. Kinematic data from a real concussion case served as boundary conditions to a subject-specific head FE model. Tissue strains were then used as input to histology-informed tissue-like models of the corpus callosum's subregions. Resulting membrane strains were eventually compared against mechanoporation thresholds to infer about the injury outcome.

In summary, this thesis increases our understanding of the possible mechanical cues behind axonal injury. By using a computational approach bridging the organ-to-molecule length scales, this work proposes a new way of non-invasively predicting axonal damage. Although further experimental evidence is required, such an approach lays the foundation for increasingly complex and potentially revealing simulations of axonal injury.

Abstract [sv]

Traumatisk hjärnskada (TBI) ses idag som ett globalt hälsoproblem. Djupare förståelse och kartläggning för hur yttre mekaniska laster påverkar hjärnvävnad och dess celler är nödvändig för att kunna vidareutveckla och förbättra skyddsutrustning och medicinsk behandling efter inträffad skada. Under de senaste decennierna har signifikanta framsteg gjorts gällande den biomekaniska grunden för TBI. Finita elementmodeller av huvud och hjärna har visat sig vara värdefulla verktyg för att öka förståelsen mellan huvudets kinematik och deformationsmönstret i hjärnan. Dessa framsteg till trots saknas dock fortfarande en omfattande patofysiologisk förståelse för hur olika längdskalor samverkar i TBI.

Huvudsyftet med denna avhandling var att öka förståelsen för hur axonskada sker på olika längdskalor. Detta innebär främst att hitta en möjlig skademekanism, samt definiera toleranser för axonskada vid olika längdskalor. För att kunna studera detta i en isolerad simuleringsmiljö, utvecklades i den första studien en kompositmodell av en axon i en finita elementuppställning. Sårbarheten hos de enskilda komponenterna i axonmodellen har i Studie I utvärderats vid laster som är representativa för ett typiskt skadescenario. Ett av huvudresultaten ur första studien var det icke-homogena och stora deformationsfältet som uppstod i axonmembranet. Detta motiverade Studie II där axonmodellen användes i serie med en dynamisk molekylmodell av axonmembranet, då det är på molekylers längdskala som mekanoporering i axonmembranet kan observeras. Med denna metod kan skadetoleranser för mekanoporering defineras i relation till töjning och töjningshastighet.

Studie III fokuserade på potentiella mekaniska skillnader hos skadetröskelnivåer från encell och vävnadsmodeller. Den finita elementmodellen av en axon expanderades till en vävnadsmodell genom att repetera axonmodellen runt sig själv genom introduktionen av periodiska randvillkor. Tröskelvärden från molekylmodellen i Studie 2 användes för att nå slutsatsen att skadetoleransen är högre för vävnadsmodellen än för enskilda axonmodellen. I Studie IV karaktäriserades den mekaniska responsen hos gliavävnad (utvärderat i en bläkfiskmodell) vid både stora deformationer och dynamiska hastigheter.

Slutligen utvecklades i Studie V ett ramverk över olika längdskalor för att analysera huvudskador i sin helhet. Kinematik från ett verkligt scenario användes som indata till en patientspecifik finita elementmodell av huvudet. Dessa töjningar på vävnadsnivå användes i en histologisk vävnadsmodell av corpus callosums subregioner. Resulterande axonmembranstöjningar jämfördes mot tröskelvärdena för mekanoporering för att till slut kunna ge en förbättrad uppskattning av eventuell skada.

Således ger denna avhandling en djupare förståelse för hur de mekaniska förloppen som leder till axonskada sker på olika längdskalor. Genom att främst använda numeriska metoder fås en ny icke-invasiv metod för att bedöma och förutse axonskada. Ytterligare experimentall validering är nödvändig, men genom studierna som genomförst i denn avhandling, läggs en grund för att genomföra mer komplexa simuleringar och potentiellt hitta fler mekanismer som leder till axonskada.

Place, publisher, year, edition, pages
Kungliga Tekniska högskolan, 2020. , p. 85
Series
TRITA-CBH-FOU ; 2020:8
Keywords [en]
Traumatic Brain Injury, Axonal Injury, Mechanoporation, Multiscale
National Category
Other Medical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-266765ISBN: 978-91-7873-431-3 (print)OAI: oai:DiVA.org:kth-266765DiVA, id: diva2:1387578
Public defence
2020-02-14, T2, Hälsovägen 11C, Huddinge, 10:00 (English)
Opponent
Supervisors
Note

QC 2020-01-22

Available from: 2020-01-22 Created: 2020-01-22 Last updated: 2020-01-22Bibliographically approved
List of papers
1. Utilizing a Structural Mechanics Approach to Assess the Primary Effects of Injury Loads Onto the Axon and Its Components
Open this publication in new window or tab >>Utilizing a Structural Mechanics Approach to Assess the Primary Effects of Injury Loads Onto the Axon and Its Components
2018 (English)In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 9, no 643, p. 1-12Article in journal (Refereed) Published
Abstract [en]

Diffuse axonal injury (DAI) occurs as a result of the transmission of rapid dynamic loads from the head to the brain and specifically to its neurons. Despite being one of the most common and most deleterious types of traumatic brain injury (TBI), the inherent cell injury mechanism is yet to be understood. Experimental observations have led to the formulation of different hypotheses, such as mechanoporation of the axolemma and microtubules (MTs) breakage. With the goal of singling out the mechanical aspect of DAI and to resolve the ambiguity behind its injury mechanism, a composite finite element (FE) model of a representative volume of an axon was developed. Once calibrated and validated against published experimental data, the axonal model was used to simulate injury scenarios. The resulting strain distributions along its components were then studied in dependence of strain rate and of typical modeling choices such as the applied MT constraints and tau proteins failure. Results show that oversimplifying the MT bundle kinematic entails a systematic attenuation (cf = 2.33) of the computed maximum MT strain. Nevertheless, altogether, results support the hypothesis of axolemma mechanoporation as a cell-injury trigger. Moreover, for the first time the interconnection between the axolemma and the MT bundle is shown to play a role in damage localization. The proposed FE axonal model is a valuable tool to understand the axonal injury mechanism from a mechanical perspective and could be used in turn for the definition of well-informed injury criteria at the tissue and organ level.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
axon axolemma microtubules
National Category
Other Medical Engineering
Research subject
Engineering Mechanics
Identifiers
urn:nbn:se:kth:diva-232859 (URN)10.3389/fneur.2018.00643 (DOI)000440810200001 ()2-s2.0-85054931609 (Scopus ID)
Funder
EU, Horizon 2020, 642662
Note

QC 20180806

Available from: 2018-08-06 Created: 2018-08-06 Last updated: 2020-01-22Bibliographically approved
2. Localized axolemma deformations suggest mechanoporation as axonal injury trigger
Open this publication in new window or tab >>Localized axolemma deformations suggest mechanoporation as axonal injury trigger
(English)In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295Article in journal (Refereed) Accepted
Abstract [en]

Traumatic brain injuries are a leading cause of morbidity and mortality worldwide. With almost 50% of traumatic brain injuries being related to axonal damage, understanding the nature of cellular level impairment is crucial. Experimental observations have so far led to the formulation of conflicting theories regarding the cellular primary injury mechanism. Disruption of the axolemma, or alternatively cytoskeletal damage has been suggested mainly as injury trigger. However, mechanoporation thresholds of generic membranes seem not to overlap with the axonal injury deformation range and microtubules appear too stiff and too weakly connected to undergo mechanical breaking. Here, we aim to shed a light on the mechanism of primary axonal injury, bridging finite element and molecular dynamics simulations. Despite the necessary level of approximation, our models can accurately describe the mechanical behavior of the unmyelinated axon and its membrane. More importantly, they give access to quantities that would be inaccessible with an experimental approach. We show that in a typical injury scenario, the axonal cortex sustains deformations large enough to entail pore formation in the adjoining lipid bilayer. The observed axonal deformation of 10-12% agree well with the thresholds proposed in the literature for axonal injury and, above all, allow us to provide quantitative evidences that do not exclude pore formation in the membrane as a result of trauma. Our findings bring to an increased knowledge of axonal injury mechanism that will have positive implications for the prevention and treatment of brain injuries.

Keywords
mechanoporation, axolemma, axonal injury, Membrane Permeability, Traumatic Brain Injury, Finite Element
National Category
Other Medical Engineering
Research subject
Medical Technology; Biological Physics; Solid Mechanics; Technology and Health
Identifiers
urn:nbn:se:kth:diva-266761 (URN)10.3389/fneur.2020.00025 (DOI)000514906900001 ()2-s2.0-85079505686 (Scopus ID)
Funder
Swedish Research Council, VR- Q13 2016-05314
Note

QCR 20200122

Available from: 2020-01-20 Created: 2020-01-20 Last updated: 2020-03-16Bibliographically approved
3. Axons Embedded in a Tissue May Withstand Larger Deformations Than Isolated Axons Before Mechanoporation Occurs
Open this publication in new window or tab >>Axons Embedded in a Tissue May Withstand Larger Deformations Than Isolated Axons Before Mechanoporation Occurs
2019 (English)In: Journal of Biomechanical Engineering, ISSN 0148-0731, E-ISSN 1528-8951, Vol. 141, no 12Article in journal (Refereed) Published
Abstract [en]

Diffuse axonal injury (DAI) is the pathological consequence of traumatic brain injury (TBI) that most of all requires a multiscale approach in order to be, first, understood and then possibly prevented. While in fact the mechanical insult usually happens at the head (or macro) level, the consequences affect structures at the cellular (or microlevel). The quest for axonal injury tolerances has so far been addressed both with experimental and computational approaches. On one hand, the experimental approach presents challenges connected to both temporal and spatial resolution in the identification of a clear axonal injury trigger after the application of a mechanical load. On the other hand, computational approaches usually consider axons as homogeneous entities and therefore are unable to make inferences about their viability, which is thought to depend on subcellular damages. Here, we propose a computational multiscale approach to investigate the onset of axonal injury in two typical experimental scenarios. We simulated single-cell and tissue stretch injury using a composite finite element axonal model in isolation and embedded in a matrix, respectively. Inferences on axonal damage are based on the comparison between axolemma strains and previously established mechanoporation thresholds. Our results show that, axons embedded in a tissue could withstand higher deformations than isolated axons before mechanoporation occurred and this is exacerbated by the increase in strain rate from 1/s to 10/s.

Place, publisher, year, edition, pages
ASME Press, 2019
Keywords
DAI, injury thresholds, mechanoporation, multiscale
National Category
Other Medical Engineering
Identifiers
urn:nbn:se:kth:diva-266763 (URN)10.1115/1.4044953 (DOI)000506878100014 ()
Funder
Swedish National Infrastructure for Computing (SNIC), SNIC2017-1-491Swedish Research Council, VR-2016-05314
Note

QC 20200122

Available from: 2020-01-20 Created: 2020-01-20 Last updated: 2020-02-17Bibliographically approved
4. Mechanical characterization of squid giant axon membrane sheath and influence of the collagenous endoneurium on its properties
Open this publication in new window or tab >>Mechanical characterization of squid giant axon membrane sheath and influence of the collagenous endoneurium on its properties
Show others...
2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, no 1, article id 8969Article in journal (Refereed) Published
Abstract [en]

To understand traumas to the nervous system, the relation between mechanical load and functional impairment needs to be explained. Cellular-level computational models are being used to capture the mechanism behind mechanically-induced injuries and possibly predict these events. However, uncertainties in the material properties used in computational models undermine the validity of their predictions. For this reason, in this study the squid giant axon was used as a model to provide a description of the axonal mechanical behavior in a large strain and high strain rate regime (ε=10%,ε⋅=1s−1), which is relevant for injury investigations. More importantly, squid giant axon membrane sheaths were isolated and tested under dynamic uniaxial tension and relaxation. From the lumen outward, the membrane sheath presents: an axolemma, a layer of Schwann cells followed by the basement membrane and a prominent layer of loose connective tissue consisting of fibroblasts and collagen. Our results highlight the load-bearing role of this enwrapping structure and provide a constitutive description that could in turn be used in computational models. Furthermore, tests performed on collagen-depleted membrane sheaths reveal both the substantial contribution of the endoneurium to the total sheath’s response and an interesting increase in material nonlinearity when the collagen in this connective layer is digested. All in all, our results provide useful insights for modelling the axonal mechanical response and in turn will lead to a better understanding of the relationship between mechanical insult and electrophysiological outcome.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Medical Engineering Mechanical Engineering
Identifiers
urn:nbn:se:kth:diva-255034 (URN)10.1038/s41598-019-45446-y (DOI)000472137700065 ()31222074 (PubMedID)2-s2.0-85067621816 (Scopus ID)
Note

QC 20190729

Available from: 2019-07-16 Created: 2019-07-16 Last updated: 2020-03-09Bibliographically approved
5. Subject-specific multiscale analysis of concussion: from ma-croscopic loads to molecular-level damage
Open this publication in new window or tab >>Subject-specific multiscale analysis of concussion: from ma-croscopic loads to molecular-level damage
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Sports concussions are a form of mild TBI caused by an impulsive force transmitted tothe head. Concussion is recognized as a complex pathophysiological process affecting thebrain at multiple scales. However, neuroimaging evidence of brain damage is currentlylacking. In the present study, a multiscale computational approach that could serve asbrain damage evidence was proposed. To outline the applicability of this framework a realconcussion case associated with an alteration of consciousness was studied. In particular,mouthguard-recorded head kinematic was input into a detailed finite element head modeltailored on the subject’s head and white matter tract morphology. Resulting tissue strainswere extracted and projected to obtain tract-oriented strains. These were then input intomicroscale axonal level models representative of the corpus callosum’s subregions to obtainaxonal membrane maximal deformations. By comparing membrane deformations againstpreviously established thresholds, axonal damage could be inferred in the superior genuand anterior midbody. This study is to be seen as a novel exploratory method for theanalysis of concussion and highlights the need for further model personalization effort aswell as characterization of brain tissue composition to better understand the mechanisticcauses behind concussion.

National Category
Other Medical Engineering
Identifiers
urn:nbn:se:kth:diva-266764 (URN)
Note

QC 20200122

Available from: 2020-01-20 Created: 2020-01-20 Last updated: 2020-01-22Bibliographically approved

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