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Axons Embedded in a Tissue May Withstand Larger Deformations Than Isolated Axons Before Mechanoporation Occurs
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Neuronic Engineering.ORCID iD: 0000-0001-6306-507x
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Neuronic Engineering.ORCID iD: 0000-0003-0125-0784
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. Vol. 141, no 12
Keywords [en]
DAI, injury thresholds, mechanoporation, multiscale
National Category
Other Medical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-266763DOI: 10.1115/1.4044953ISI: 000506878100014OAI: oai:DiVA.org:kth-266763DiVA, id: diva2:1386977
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
In thesis
1. Definition of axonal injury tolerances across scales: A computational multiscale approach
Open this publication in new window or tab >>Definition of axonal injury tolerances across scales: A computational multiscale approach
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
Traumatic Brain Injury, Axonal Injury, Mechanoporation, Multiscale
National Category
Other Medical Engineering
Identifiers
urn:nbn:se:kth:diva-266765 (URN)978-91-7873-431-3 (ISBN)
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

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