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  <front>
    <journal-meta>
      <journal-id journal-id-type="publisher-id">JMBE</journal-id>
      <journal-id journal-id-type="nlm-ta">JMIR Biomed Eng</journal-id>
      <journal-title>JMIR Biomedical Engineering</journal-title>
      <issn pub-type="epub">2561-3278</issn>
      <publisher>
        <publisher-name>JMIR Publications</publisher-name>
        <publisher-loc>Toronto, Canada</publisher-loc>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id">v9i1e48146</article-id>
      <article-id pub-id-type="pmid">38875683</article-id>
      <article-id pub-id-type="doi">10.2196/48146</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Review</subject>
        </subj-group>
        <subj-group subj-group-type="article-type">
          <subject>Review</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Finite Element Analysis for Degenerative Cervical Myelopathy: Scoping Review of the Current Findings and Design Approaches, Including Recommendations on the Choice of Material Properties</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="editor">
          <name>
            <surname>Leung</surname>
            <given-names>Tiffany</given-names>
          </name>
        </contrib>
      </contrib-group>
      <contrib-group>
        <contrib contrib-type="reviewer">
          <name>
            <surname>Arab-Zozani</surname>
            <given-names>Morteza</given-names>
          </name>
        </contrib>
        <contrib contrib-type="reviewer">
          <name>
            <surname>Perez Sanpablo</surname>
            <given-names>AlbertoIsaac</given-names>
          </name>
        </contrib>
      </contrib-group>
      <contrib-group>
        <contrib id="contrib1" contrib-type="author" corresp="yes">
          <name name-style="western">
            <surname>Davies</surname>
            <given-names>Benjamin</given-names>
          </name>
          <degrees>BSc, MBChB (Hons), MPhil</degrees>
          <xref rid="aff1" ref-type="aff">1</xref>
          <address>
            <institution>Department of Medicine</institution>
            <institution>University of Cambridge</institution>
            <addr-line>Addenbrooke’s Hospital, Hills Road</addr-line>
            <addr-line>Cambridge, CB2 0QQ</addr-line>
            <country>United Kingdom</country>
            <phone>44 07766692608</phone>
            <email>bd375@cam.ac.uk</email>
          </address>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0003-0591-5069</ext-link>
        </contrib>
        <contrib id="contrib2" contrib-type="author">
          <name name-style="western">
            <surname>Schaefer</surname>
            <given-names>Samuel</given-names>
          </name>
          <degrees>MEng</degrees>
          <xref rid="aff2" ref-type="aff">2</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0002-2935-8239</ext-link>
        </contrib>
        <contrib id="contrib3" contrib-type="author">
          <name name-style="western">
            <surname>Rafati Fard</surname>
            <given-names>Amir</given-names>
          </name>
          <degrees>BA</degrees>
          <xref rid="aff1" ref-type="aff">1</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0003-1804-2586</ext-link>
        </contrib>
        <contrib id="contrib4" contrib-type="author">
          <name name-style="western">
            <surname>Newcombe</surname>
            <given-names>Virginia</given-names>
          </name>
          <degrees>MD, PhD</degrees>
          <xref rid="aff1" ref-type="aff">1</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0001-6044-9035</ext-link>
        </contrib>
        <contrib id="contrib5" contrib-type="author">
          <name name-style="western">
            <surname>Sutcliffe</surname>
            <given-names>Michael</given-names>
          </name>
          <degrees>MA, PhD</degrees>
          <xref rid="aff2" ref-type="aff">2</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0001-9729-4460</ext-link>
        </contrib>
      </contrib-group>
      <aff id="aff1">
        <label>1</label>
        <institution>Department of Medicine</institution>
        <institution>University of Cambridge</institution>
        <addr-line>Cambridge</addr-line>
        <country>United Kingdom</country>
      </aff>
      <aff id="aff2">
        <label>2</label>
        <institution>Department of Engineering</institution>
        <institution>University of Cambridge</institution>
        <addr-line>Cambridge</addr-line>
        <country>United Kingdom</country>
      </aff>
      <author-notes>
        <corresp>Corresponding Author: Benjamin Davies <email>bd375@cam.ac.uk</email></corresp>
      </author-notes>
      <pub-date pub-type="collection">
        <year>2024</year>
      </pub-date>
      <pub-date pub-type="epub">
        <day>28</day>
        <month>3</month>
        <year>2024</year>
      </pub-date>
      <volume>9</volume>
      <elocation-id>e48146</elocation-id>
      <history>
        <date date-type="received">
          <day>13</day>
          <month>4</month>
          <year>2023</year>
        </date>
        <date date-type="rev-request">
          <day>28</day>
          <month>8</month>
          <year>2023</year>
        </date>
        <date date-type="rev-recd">
          <day>31</day>
          <month>10</month>
          <year>2023</year>
        </date>
        <date date-type="accepted">
          <day>15</day>
          <month>2</month>
          <year>2024</year>
        </date>
      </history>
      <copyright-statement>©Benjamin Davies, Samuel Schaefer, Amir Rafati Fard, Virginia Newcombe, Michael Sutcliffe. Originally published in JMIR Biomedical Engineering (http://biomsedeng.jmir.org), 28.03.2024.</copyright-statement>
      <copyright-year>2024</copyright-year>
      <license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/">
        <p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Biomedical Engineering, is properly cited. The complete bibliographic information, a link to the original publication on https://biomedeng.jmir.org/, as well as this copyright and license information must be included.</p>
      </license>
      <self-uri xlink:href="https://biomedeng.jmir.org/2024/1/e48146" xlink:type="simple"/>
      <abstract>
        <sec sec-type="background">
          <title>Background</title>
          <p>Degenerative cervical myelopathy (DCM) is a slow-motion spinal cord injury caused via chronic mechanical loading by spinal degenerative changes. A range of different degenerative changes can occur. Finite element analysis (FEA) can predict the distribution of mechanical stress and strain on the spinal cord to help understand the implications of any mechanical loading. One of the critical assumptions for FEA is the behavior of each anatomical element under loading (ie, its material properties).</p>
        </sec>
        <sec sec-type="objective">
          <title>Objective</title>
          <p>This scoping review aims to undertake a structured process to select the most appropriate material properties for use in DCM FEA. In doing so, it also provides an overview of existing modeling approaches in spinal cord disease and clinical insights into DCM.</p>
        </sec>
        <sec sec-type="methods">
          <title>Methods</title>
          <p>We conducted a scoping review using qualitative synthesis. Observational studies that discussed the use of FEA models involving the spinal cord in either health or disease (including DCM) were eligible for inclusion in the review. We followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. The MEDLINE and Embase databases were searched to September 1, 2021. This was supplemented with citation searching to retrieve the literature used to define material properties. Duplicate title and abstract screening and data extraction were performed. The quality of evidence was appraised using the quality assessment tool we developed, adapted from the Newcastle-Ottawa Scale, and shortlisted with respect to DCM material properties, with a final recommendation provided. A qualitative synthesis of the literature is presented according to the Synthesis Without Meta-Analysis reporting guidelines.</p>
        </sec>
        <sec sec-type="results">
          <title>Results</title>
          <p>A total of 60 papers were included: 41 (68%) “FEA articles” and 19 (32%) “source articles.” Most FEA articles (33/41, 80%) modeled the gray matter and white matter separately, with models typically based on tabulated data or, less frequently, a hyperelastic Ogden variant or linear elastic function. Of the 19 source articles, 14 (74%) were identified as describing the material properties of the spinal cord, of which 3 (21%) were considered most relevant to DCM. Of the 41 FEA articles, 15 (37%) focused on DCM, of which 9 (60%) focused on ossification of the posterior longitudinal ligament. Our aggregated results of DCM FEA indicate that spinal cord loading is influenced by the pattern of degenerative changes, with decompression alone (eg, laminectomy) sufficient to address this as opposed to decompression combined with other procedures (eg, laminectomy and fusion).</p>
        </sec>
        <sec sec-type="conclusions">
          <title>Conclusions</title>
          <p>FEA is a promising technique for exploring the pathobiology of DCM and informing clinical care. This review describes a structured approach to help future investigators deploy FEA for DCM. However, there are limitations to these recommendations and wider uncertainties. It is likely that these will need to be overcome to support the clinical translation of FEA to DCM.</p>
        </sec>
      </abstract>
      <kwd-group>
        <kwd>scoping review</kwd>
        <kwd>fine element analysis</kwd>
        <kwd>cervical spine</kwd>
        <kwd>spinal cord</kwd>
        <kwd>degenerative cervical myelopathy</kwd>
      </kwd-group>
    </article-meta>
  </front>
  <body>
    <sec sec-type="introduction">
      <title>Introduction</title>
      <p>Degenerative cervical myelopathy (DCM) occurs when arthritic changes to the structure of the cervical spine injure the spinal cord, causing a slowly progressive spinal cord injury (SCI) [<xref ref-type="bibr" rid="ref1">1</xref>]. This leads to a range of different symptoms that can affect the whole body, including loss of dexterity, imbalance, altered sensation, bladder and bowel dysfunction, and pain [<xref ref-type="bibr" rid="ref2">2</xref>]. Although DCM is estimated to affect 1 in 50 adults, &#60;20% are estimated to receive a diagnosis. This is likely, in part, as most are only mildly affected [<xref ref-type="bibr" rid="ref3">3</xref>,<xref ref-type="bibr" rid="ref4">4</xref>]. Treatment is currently limited to surgery but, due to inherent risks, is reserved for those with progressive or moderate-to-severe disease [<xref ref-type="bibr" rid="ref5">5</xref>]. Notably, &#60;5% of patients with DCM will make a complete recovery after surgery, and instead are left with lifelong disabilities and dependence having among the lowest quality of life scores of any disease [<xref ref-type="bibr" rid="ref6">6</xref>,<xref ref-type="bibr" rid="ref7">7</xref>]. Consequently, this was recently estimated to cost GBP £0.7 billion (approximately US $0.9 billion) per year [<xref ref-type="bibr" rid="ref8">8</xref>].</p>
      <p>The etiology and pathophysiology of DCM are poorly understood [<xref ref-type="bibr" rid="ref1">1</xref>,<xref ref-type="bibr" rid="ref9">9</xref>]. At a macroscopic level, this is a cohort that displays progressive cervical myelopathy with degenerative changes to the structure of their cervical spine, typically causing some deformation of the spinal cord on magnetic resonance imaging (MRI), which responds to decompressive surgery. This led to the hypothesis that DCM is triggered by a chronic mechanical injury, specifically compression loading.</p>
      <p>However, this is likely to be an oversimplification. Spinal cord compression is most commonly an incidental finding [<xref ref-type="bibr" rid="ref3">3</xref>]; the amount of compression visualized on the MRI poorly correlates with the disease severity and does not predict the treatment response [<xref ref-type="bibr" rid="ref10">10</xref>-<xref ref-type="bibr" rid="ref12">12</xref>]. Moreover, many other forms of mechanical loading also occur, including stretching or shear loading. These are recognized to be capable of causing tissue injury independently [<xref ref-type="bibr" rid="ref1">1</xref>]. For example, stretching is considered the etiology of myelopathy in tethered cord syndrome and some forms of deformity [<xref ref-type="bibr" rid="ref13">13</xref>]. Consequently, it is more likely that the mechanical trigger in DCM is the interaction of these mechanical forces rather than one alone. As the structural changes within the spine highly vary between patients, this is likely to be a very individualized phenomenon [<xref ref-type="bibr" rid="ref14">14</xref>]. This presents a problem for clinical practice, as conventional diagnostic tests such as MRI cannot measure mechanical stress; however, the goal of surgery is to alleviate it [<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref15">15</xref>].</p>
      <p>Finite element analysis (FEA) is an engineering technique that uses a computational model to derive the extent and severity of mechanical stress from an assumed loading [<xref ref-type="bibr" rid="ref16">16</xref>]. This has frequently been applied to health care, including, to some extent, SCI and, more recently, DCM [<xref ref-type="bibr" rid="ref16">16</xref>-<xref ref-type="bibr" rid="ref18">18</xref>]. FEA could have important applications in DCM, both to improve our understanding of the pathobiology and to represent an individual’s injury and objectively inform surgical strategy.</p>
      <p>To perform an FEA, a computer model incorporating the geometry, motion, and material properties of each structure must be created [<xref ref-type="bibr" rid="ref17">17</xref>]. Geometry and motion, to a large extent, can be defined based on an individual’s clinical imaging. However, the material properties must be chosen from other sources. These choices will influence the results of the FEA. For spinal cord FEA to date, these choices have been made on a project-by-project basis, typically informed by the experience of the investigators, their interpretation and knowledge of the literature, and their specific project aims. To inform the development of FEA for DCM, we adopted an iterative approach using a scoping review methodology with the following aims:</p>
      <list list-type="bullet">
        <list-item>
          <p>To describe how FEA models have been constructed with respect to spinal cord disease</p>
        </list-item>
        <list-item>
          <p>To identify and appraise the experimental literature that has informed their material property choices to make recommendations on the material properties for DCM FEA</p>
        </list-item>
        <list-item>
          <p>To aggregate the findings from studies using FEA to explore DCM.</p>
        </list-item>
      </list>
      <p>To the best of our knowledge, this represents a unique approach to selecting the material properties for a clinical FEA model and may represent an exemplar for similar initiatives.</p>
    </sec>
    <sec sec-type="methods">
      <title>Methods</title>
      <p>A scoping review methodology was considered most appropriate to meet these objectives [<xref ref-type="bibr" rid="ref19">19</xref>]. This scoping review was reported in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines (<xref ref-type="supplementary-material" rid="app1">Multimedia Appendix 1</xref>).</p>
      <sec>
        <title>Search Strategy</title>
        <p>The search was conducted using a modified population, interventions, comparisons, and outcomes strategy, which states that the research question for a review must include the population, intervention, comparison, and outcome. Our research question was, “what are the current findings and design approaches for FEA in DCM?”, with the population being patients with DCM, intervention being FEA, and outcomes being current findings and design approaches. To more comprehensively guide future decisions regarding the application of FEA methods to DCM, we broadened our inclusion criteria to incorporate any study that applied FEA to the spinal cord (in either health or disease). Consequently, the search terms were designed to capture observational studies that had developed FEA models that included the spinal cord in either health or disease, including DCM (<xref ref-type="supplementary-material" rid="app2">Multimedia Appendix 2</xref>). Searches were conducted from inception (February 12, 2021) to September 1, 2021, in the MEDLINE and Embase databases. Search sensitivity was evaluated using 5 papers known to meet the inclusion criteria; all papers were successfully captured [<xref ref-type="bibr" rid="ref18">18</xref>,<xref ref-type="bibr" rid="ref20">20</xref>-<xref ref-type="bibr" rid="ref23">23</xref>].</p>
      </sec>
      <sec>
        <title>Inclusion and Exclusion Criteria</title>
        <p>Papers were considered eligible for inclusion if they were observational studies that discussed the use of FEA models that included the spinal cord of humans or animals in either health or disease, including DCM.</p>
        <p>Papers were excluded if they were written in a language other than English, did not use FEA models, or did not include the spinal cord in the FEA model. Furthermore, systematic reviews, scoping reviews, editorials, and abstracts were excluded.</p>
      </sec>
      <sec>
        <title>Study Screening and Data Extraction</title>
        <p>Two reviewers (BMD and SS) independently performed title and abstract screening with blinding using Rayyan (Rayyan Systems Inc). A pilot screen of 100 publications was conducted to ensure concordance between reviewers. Any disagreements following unblinding were resolved by discussion between the reviewers until mutual agreement was reached. In this review, papers identified through our search strategy are termed “FEA articles”.</p>
        <p>From the included FEA articles, the references used to justify a structure’s material properties were also screened to identify experimental studies reporting original data acquired from physical tissue tests. Studies exploring behavior computationally but including their original physical experiments, even if published elsewhere, were included. Studies that explored properties solely on a computational basis were excluded. This forward search continued within the references of a referenced study if the reference did not meet this criterion and had cited an alternative source.</p>
        <p>Papers were retrieved for full-text screening and data extraction using a piloted pro forma. Data extracted from the papers included: author, year of publication, country, study objectives, study design (eg, human or animal study), disease of interest (if any), spinal segment (eg, cervical, thoracic, and lumbar), reference for anatomy (eg, cadaveric specimen and imaging), and details of how the FEA model was developed and validated (including the material properties of the anatomical elements).</p>
        <p>Data extraction focused on the properties specifically referenced by the original FEA models and may not have included all the material properties discussed in the paper. To understand an investigator’s approach to model development, these were distinguished as those used to define the model a priori (ie, referenced data and the choice of material law and selected coefficients) or those used to validate the final model (if performed). However, for the purpose of selecting data to inform an FEA model, these references were aggregated and termed as “source articles” in this review.</p>
        <p>In the absence of a standard quality assessment tool for experimental studies of biomechanics, we developed a classification to help appraise source articles that are most appropriate for a DCM FEA model [<xref ref-type="bibr" rid="ref24">24</xref>]. This included a risk of bias assessment adapted from the Newcastle-Ottawa Scale, focusing on selection and reporting bias (<xref ref-type="supplementary-material" rid="app3">Multimedia Appendix 3</xref>) [<xref ref-type="bibr" rid="ref25">25</xref>].</p>
      </sec>
      <sec>
        <title>Data Analysis and Reporting</title>
        <p>Due to significant heterogeneity between methodologies, meta-analysis was not possible, and a qualitative Synthesis Without Meta-Analysis (SWiM) was instead performed. Data were aggregated, where applicable, qualitatively, quantitatively, or using frequency statistics, as per the SWiM guidelines [<xref ref-type="bibr" rid="ref26">26</xref>].</p>
        <p>Given the small field size, with many papers published by single groups, citation networks were created to graphically consider which choices were made across the field and how they were informed. Using this framework and our judgment, we ranked source articles into approximate tertiles. For FEA articles that had cited top-source articles and represented the material properties using an equation, the performance of this equation was further evaluated graphically by generating stress-strain curves. These were exclusively either linear or hyperelastic. For models using a linear elastic equation, the Young modulus was used as the gradient of the stress-strain curve. For models using a hyperelastic equation, a 3×3 element cube was created using ABAQUS (Dassault Systèmes). The cube was stretched uniaxially, with no constraint applied in the orthogonal directions, linearly increasing the nominal strain in increments of 0.04 to a maximum of 0.4. The outputs of this model were then applied true stress as a function of the applied true strain. Finally, any primary clinical papers that conducted FEA for the investigation of DCM were aggregated separately and analyzed.</p>
        <p>Data were displayed using a range of plots constructed using R Studio (version 4.0.3; Posit).</p>
      </sec>
    </sec>
    <sec sec-type="results">
      <title>Results</title>
      <sec>
        <title>Overall Approach of FEA Models of Spinal Cord Disease: Anatomy, Geometry, Motion, and Validation</title>
        <p>The search returned 597 articles, of which 155 (25.9%) were duplicates (<xref rid="figure1" ref-type="fig">Figure 1</xref>). Following screening, 41 FEA articles were eligible for inclusion, of which 32 (78%) modeled the human spinal cord; a further 45 (7.54%) source articles were identified through citation search, of which 19 (42%) were shortlisted as suitable. Of the FEA articles, approximately half (21/41, 51%) focused on SCI [<xref ref-type="bibr" rid="ref27">27</xref>-<xref ref-type="bibr" rid="ref47">47</xref>]; 34% (14/41) on DCM [<xref ref-type="bibr" rid="ref18">18</xref>,<xref ref-type="bibr" rid="ref20">20</xref>-<xref ref-type="bibr" rid="ref22">22</xref>,<xref ref-type="bibr" rid="ref48">48</xref>-<xref ref-type="bibr" rid="ref57">57</xref>]; and 5% (2/41) each on scoliosis [<xref ref-type="bibr" rid="ref58">58</xref>,<xref ref-type="bibr" rid="ref59">59</xref>], syringomyelia [<xref ref-type="bibr" rid="ref60">60</xref>,<xref ref-type="bibr" rid="ref61">61</xref>], and flexion myelopathy [<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref63">63</xref>]. Most models (25/41, 61%) included only the spinal cord, whereas 24% (10/41) included the surrounding anatomy at multiple vertebral levels, and 17% (7/41) included the surrounding anatomy at only 1 motion segment (ie, 2 adjacent vertebrae). Physiological movement of the spine (flexion and extension) was incorporated into 17% (7/41) of the models, but none evaluated spinal cord oscillation. This was equally likely among the DCM and SCI models (<xref ref-type="supplementary-material" rid="app4">Multimedia Appendix 4</xref>).</p>
        <p>The anatomy of each model was built using a combination of imaging and cadaveric data in 27% (11/41) of the FEA articles. Typically, imaging was used for bones and cadavers for soft tissues, including the spinal cord. This included an open-source reference library called BodyWorks [<xref ref-type="bibr" rid="ref64">64</xref>] and a review of spinal cord geometry [<xref ref-type="bibr" rid="ref65">65</xref>]. MRI was used to define the spinal cord specifically in 20% (8/41) of the FEA articles.</p>
        <fig id="figure1" position="float">
          <label>Figure 1</label>
          <caption>
            <p>PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram. FEA: finite element analysis.</p>
          </caption>
          <graphic xlink:href="biomedeng_v9i1e48146_fig1.png" alt-version="no" mimetype="image" position="float" xlink:type="simple"/>
        </fig>
        <p>For most FEA articles (33/41, 80%), the spinal cord was modeled as gray matter and white matter separately and had a defined pial layer (26/41, 63%) or was encased within the dural layer (26/41, 63%). Defined pial and dural layers were used in combination in only half of these articles (13/41, 32%). Cerebrospinal fluid (CSF) was specifically modeled in 41% (17/41) of the FEA articles, while other elements were variably included. This choice was independent of the disease and publication date (<xref ref-type="supplementary-material" rid="app4">Multimedia Appendix 4</xref>). Elements were modeled using solid shell elements, unless specified differently in the Material Properties of Anatomical Elements With Recommendations for DCM FEA section.</p>
        <p>Validation methods were specified in 63% (26/41) of the FEA articles, with 15% (6/41) using their own experiments and 9% (20/41) using literature (<xref ref-type="supplementary-material" rid="app5">Multimedia Appendix 5</xref>). These references pointed to 17 articles, of which 7 (42%) provided material property data for the spinal cord in healthy circumstances and 3 (18%) in traumatic SCI circumstances. Of the remaining 17 articles, 4 (24%) described motion of the spine [<xref ref-type="bibr" rid="ref66">66</xref>-<xref ref-type="bibr" rid="ref69">69</xref>] and 1 (6%) described the spinal cord in flexion and extension [<xref ref-type="bibr" rid="ref70">70</xref>]. Of the 9 articles providing information on healthy spinal cord properties, 7 (78%) were also used in other studies to inform the selection of material property. No DCM-specific validation data sets were identified.</p>
      </sec>
      <sec>
        <title>Material Properties of Anatomical Elements With Recommendations for DCM FEA</title>
        <sec>
          <title>Spinal Cord</title>
          <p>The material properties of the whole spinal cord were defined in 22% (9/41) of the FEA articles. This was rarely justified, but if so, qualified by its uncertain significance [<xref ref-type="bibr" rid="ref71">71</xref>,<xref ref-type="bibr" rid="ref72">72</xref>]. Typically, a hyperelastic Ogden variant (4/9, 44%) or a linear elastic (3/9, 33%) function was used.</p>
          <p>For the remaining models, gray and white matter were modeled separately, except for the article that explored the impact of a range of white matter material properties, where the material law applied to gray matter was the same as that of white matter. The remaining 32 models were mostly based on tabulated data from the studies by Ichihara et al [<xref ref-type="bibr" rid="ref72">72</xref>,<xref ref-type="bibr" rid="ref73">73</xref>], and less frequently, Bilston and Thibault [<xref ref-type="bibr" rid="ref74">74</xref>], Tunturi [<xref ref-type="bibr" rid="ref75">75</xref>], and Ozawa et al [<xref ref-type="bibr" rid="ref76">76</xref>]. Alternatively, a hyperelastic Ogden variant (10/41, 24%) or a linear elastic (4/41, 10%) function was used.</p>
          <p>A total of 2 studies specifically compared different material properties with respect to a transverse contusion model of SCI. Jannesar et al [<xref ref-type="bibr" rid="ref38">38</xref>] explored white matter properties on the basis that single constitutive models may not account for the dynamic (viscoelastic) and anisotropic properties. They identified that this could be improved by adding reinforcing functions. A second order reduced polynomial hyperelastic function combined with a quadratic reinforcing function in a 4-term Prony series performed best (0.89&#60;<italic>R</italic><sup>2</sup>&#60;0.99), although this was principally in relation to the high strain rates of an SCI. Fournely et al [<xref ref-type="bibr" rid="ref45">45</xref>] used a first-order Ogden function but varied the stiffness of the gray matter with respect to the white matter. Although this fell within the range of the validation data set, they observed differing responses to the load. When the gray matter was stiffer than the white matter, strain distribution was more diffuse and maximal within the white matter. When the stiffness was equivalent, strain was localized to the impact site. When the white matter was stiffer than the gray matter, strain was less localized, maximal within the gray matter and involved the contralateral gray matter. This was the principal factor determining behavior, ahead of other factors explored, including spinal cord diameter, curvature, and impactor angle.</p>
          <p>A total of 2 studies similarly explored the implications of different gray and white matter material properties with respect to DCM, with similar findings discussed in the Findings From the FEA Studies of DCM section [<xref ref-type="bibr" rid="ref34">34</xref>,<xref ref-type="bibr" rid="ref50">50</xref>].</p>
          <p>A total of 14 source articles were identified describing the material properties of the spinal cord or its subcomponents (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref> [<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref72">72</xref>-<xref ref-type="bibr" rid="ref75">75</xref>,<xref ref-type="bibr" rid="ref77">77</xref>-<xref ref-type="bibr" rid="ref90">90</xref>]), of which 3 (21%) were shortlisted with relevance to an FEA for DCM [<xref ref-type="bibr" rid="ref72">72</xref>-<xref ref-type="bibr" rid="ref74">74</xref>]. Their interpretations varied across studies (<xref rid="figure2" ref-type="fig">Figure 2</xref>). The choice of material laws and values of those who directly cited the prioritized source articles and separately distinguished gray and white matter are listed in <xref ref-type="table" rid="table1">Tables 1</xref>-<xref ref-type="table" rid="table2">2</xref>. Broadly, these align with the source articles; however, there are differences across the strain range (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>). Of these FEA articles representing material properties with an equation, studies by Jannesar et al [<xref ref-type="bibr" rid="ref29">29</xref>] and Khuyagbaatar et al [<xref ref-type="bibr" rid="ref53">53</xref>] were selected as these were most aligned for gray matter and white matter, respectively.</p>
          <fig id="figure2" position="float">
            <label>Figure 2</label>
            <caption>
              <p>Network analysis of finite element analysis models, which is linked to a shortlisted source article, for the white matter (A) and gray matter (B) or the spinal cord as a whole (C). The original finite element analysis models are represented by their choice of material law as a star (linear elastic), square (hyperelastic), diamond (tabulated), or triangle (other) and their disease of interest as degenerative cervical myelopathy (DCM; red), spinal cord injury (SCI; blue), or other (green). These link to the primary source articles (dots). An intermediate article, that is, the one that did not include primary experimental data, is pale gray. A shortlisted source article is black. Each figure is additionally available as an interactive file; refer to <xref ref-type="supplementary-material" rid="app7">Multimedia Appendix 7</xref>. The higher resolution version of this figure is available in <xref ref-type="supplementary-material" rid="app8">Multimedia Appendix 8</xref>.</p>
            </caption>
            <graphic xlink:href="biomedeng_v9i1e48146_fig2.png" alt-version="no" mimetype="image" position="float" xlink:type="simple"/>
          </fig>
          <table-wrap position="float" id="table1">
            <label>Table 1</label>
            <caption>
              <p>Extracted material equations for the gray matter.</p>
            </caption>
            <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
              <col width="180"/>
              <col width="90"/>
              <col width="130"/>
              <col width="110"/>
              <col width="110"/>
              <col width="80"/>
              <col width="60"/>
              <col width="60"/>
              <col width="80"/>
              <col width="100"/>
              <thead>
                <tr valign="top">
                  <td>Study, year</td>
                  <td>Pathology</td>
                  <td>Reference</td>
                  <td>Law</td>
                  <td>Variant</td>
                  <td>E<sup>a</sup> (MPa)</td>
                  <td>ν<sup>b</sup></td>
                  <td>α<sup>c</sup></td>
                  <td>μ<sup>d</sup> (MPa)</td>
                  <td>D<sup>e</sup> (MPa<sup>−</sup><sup>1</sup>)</td>
                </tr>
              </thead>
              <tbody>
                <tr valign="top">
                  <td>Jannesar et al [<xref ref-type="bibr" rid="ref29">29</xref>], 2021<sup>f</sup></td>
                  <td>SCI<sup>g</sup></td>
                  <td>Ichihara et al [<xref ref-type="bibr" rid="ref72">72</xref>], 2003</td>
                  <td>Hyperelastic</td>
                  <td>Ogden, first Order</td>
                  <td>—<sup>h</sup></td>
                  <td>0.49</td>
                  <td>10.57</td>
                  <td>0.0445</td>
                  <td>
                    <italic>0.905<sup>i,j</sup></italic>
                  </td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref53">53</xref>], 2017</td>
                  <td>DCM<sup>k</sup></td>
                  <td>Ichihara et al [<xref ref-type="bibr" rid="ref73">73</xref>], 2001</td>
                  <td>Hyperelastic</td>
                  <td>Ogden, first order</td>
                  <td>—</td>
                  <td>
                    <italic>0.45</italic>
                  </td>
                  <td>14.7</td>
                  <td>0.0041</td>
                  <td>50.5</td>
                </tr>
                <tr valign="top">
                  <td>Jannesar et al [<xref ref-type="bibr" rid="ref38">38</xref>], 2016</td>
                  <td>SCI</td>
                  <td>Ichihara et al [<xref ref-type="bibr" rid="ref72">72</xref>], 2003</td>
                  <td>Hyperelastic</td>
                  <td>Ogden, first order</td>
                  <td>—</td>
                  <td>0.45</td>
                  <td>7.52</td>
                  <td>0.0306</td>
                  <td>6.77</td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref39">39</xref>], 2016</td>
                  <td>SCI</td>
                  <td>Ichihara et al [<xref ref-type="bibr" rid="ref73">73</xref>], 2001</td>
                  <td>Hyperelastic</td>
                  <td>Ogden, first order</td>
                  <td>—</td>
                  <td>
                    <italic>0.45</italic>
                  </td>
                  <td>14.7</td>
                  <td>0.0041</td>
                  <td>50.5</td>
                </tr>
                <tr valign="top">
                  <td>Czyz et al [<xref ref-type="bibr" rid="ref42">42</xref>], 2008</td>
                  <td>SCI</td>
                  <td>Ichihara et al [<xref ref-type="bibr" rid="ref72">72</xref>], 2003</td>
                  <td>Linear elastic</td>
                  <td>—</td>
                  <td>0.656</td>
                  <td>0.499</td>
                  <td>—</td>
                  <td>
                    <italic>0.2188</italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Maikos et al [<xref ref-type="bibr" rid="ref43">43</xref>], 2008</td>
                  <td>SCI</td>
                  <td>Bilston and Thibault [<xref ref-type="bibr" rid="ref74">74</xref>], 1996</td>
                  <td>Hyperelastic</td>
                  <td>Ogden, first order</td>
                  <td>—</td>
                  <td>0.45</td>
                  <td>4.7</td>
                  <td>0.0320</td>
                  <td>6.47</td>
                </tr>
                <tr valign="top">
                  <td>Scifert et al [<xref ref-type="bibr" rid="ref44">44</xref>], 2002</td>
                  <td>SCI</td>
                  <td>Bilston and Thibault [<xref ref-type="bibr" rid="ref74">74</xref>], 1996</td>
                  <td>Linear elastic</td>
                  <td>—</td>
                  <td>0.0667</td>
                  <td>0.499</td>
                  <td>—</td>
                  <td>
                    <italic>0.0222</italic>
                  </td>
                  <td>—</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="table1fn1">
                <p><sup>a</sup>E: Young modulus.</p>
              </fn>
              <fn id="table1fn2">
                <p><sup>b</sup>ν: Poisson ratio. Where missing, the value of ν was assumed to be 0.45.</p>
              </fn>
              <fn id="table1fn3">
                <p><sup>c</sup>α: material exponent parameter.</p>
              </fn>
              <fn id="table1fn4">
                <p><sup>d</sup>μ: ground shear hyperelastic modulus.</p>
              </fn>
              <fn id="table1fn5">
                <p><sup>e</sup>D: compressibility constant.</p>
              </fn>
              <fn id="table1fn6">
                <p><sup>f</sup>The single preferred source of the authors based on modeling (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>), where a range of equations were put forward.</p>
              </fn>
              <fn id="table1fn7">
                <p><sup>g</sup>SCI: spinal cord injury.</p>
              </fn>
              <fn id="table1fn8">
                <p><sup>h</sup>Not available.</p>
              </fn>
              <fn id="table1fn9">
                <p><sup>i</sup>Denotes a suspected error in original text and input value given.</p>
              </fn>
              <fn id="table1fn10">
                <p><sup>j</sup>Values in italics are input based on the identity for isotropic materials, D=3(1-2ν)/(μ{1+ν}), and for linear elastic, μ=E/(2{1+ν}).</p>
              </fn>
              <fn id="table1fn11">
                <p><sup>k</sup>DCM: degenerative cervical myelopathy.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
          <table-wrap position="float" id="table2">
            <label>Table 2</label>
            <caption>
              <p>Extracted material equations for the white matter.</p>
            </caption>
            <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
              <col width="180"/>
              <col width="90"/>
              <col width="130"/>
              <col width="110"/>
              <col width="110"/>
              <col width="80"/>
              <col width="60"/>
              <col width="60"/>
              <col width="80"/>
              <col width="100"/>
              <thead>
                <tr valign="top">
                  <td>Study, year</td>
                  <td>Pathology</td>
                  <td>Reference</td>
                  <td>Law</td>
                  <td>Variant</td>
                  <td>E<sup>a</sup> (MPa)</td>
                  <td>ν<sup>b</sup></td>
                  <td>α<sup>c</sup></td>
                  <td>μ<sup>d</sup> (MPa)</td>
                  <td>D<sup>e</sup> (MPa<sup>−</sup><sup>1</sup>)</td>
                </tr>
              </thead>
              <tbody>
                <tr valign="top">
                  <td>Liang et al [<xref ref-type="bibr" rid="ref48">48</xref>], 2021</td>
                  <td>DCM<sup>f</sup></td>
                  <td>Ichihara et al [<xref ref-type="bibr" rid="ref73">73</xref>], 2001</td>
                  <td>Linear elastic</td>
                  <td>—<sup>g</sup></td>
                  <td>4.2</td>
                  <td>0.45</td>
                  <td>—</td>
                  <td>
                    <italic>1.4483<sup>h</sup></italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref52">52</xref>], 2017</td>
                  <td>DCM</td>
                  <td>Ichihara et al [<xref ref-type="bibr" rid="ref73">73</xref>], 2001</td>
                  <td>Hyperelastic</td>
                  <td>Ogden, first order</td>
                  <td>—</td>
                  <td>
                    <italic>0.45</italic>
                  </td>
                  <td>12.5</td>
                  <td>0.0040</td>
                  <td>51.7</td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref39">39</xref>], 2016</td>
                  <td>SCI<sup>i</sup></td>
                  <td>Ichihara et al [<xref ref-type="bibr" rid="ref73">73</xref>], 2001</td>
                  <td>Hyperelastic</td>
                  <td>Ogden, first order</td>
                  <td>—</td>
                  <td>
                    <italic>0.45</italic>
                  </td>
                  <td>12.5</td>
                  <td>0.0040</td>
                  <td>51.7</td>
                </tr>
                <tr valign="top">
                  <td>Czyz et al [<xref ref-type="bibr" rid="ref42">42</xref>], 2008</td>
                  <td>SCI</td>
                  <td>Ichihara et al [<xref ref-type="bibr" rid="ref72">72</xref>], 2003</td>
                  <td>Linear elastic</td>
                  <td>—</td>
                  <td>0.277</td>
                  <td>0.499</td>
                  <td>—</td>
                  <td>
                    <italic>0.0924</italic>
                  </td>
                  <td>— </td>
                </tr>
                <tr valign="top">
                  <td>Maikos et al [<xref ref-type="bibr" rid="ref43">43</xref>], 2008</td>
                  <td>SCI</td>
                  <td>Bilston and Thibault [<xref ref-type="bibr" rid="ref74">74</xref>], 1996</td>
                  <td>Hyperelastic</td>
                  <td>Ogden, first order</td>
                  <td>—</td>
                  <td>0.45</td>
                  <td>4.7</td>
                  <td>0.0320</td>
                  <td>6.47</td>
                </tr>
                <tr valign="top">
                  <td>Scifert et al [<xref ref-type="bibr" rid="ref44">44</xref>], 2002</td>
                  <td>SCI</td>
                  <td>Bilston and Thibault [<xref ref-type="bibr" rid="ref74">74</xref>], 1996</td>
                  <td>Linear elastic</td>
                  <td>—</td>
                  <td>0.0667</td>
                  <td>0.499</td>
                  <td>—</td>
                  <td>
                    <italic>0.0222</italic>
                  </td>
                  <td>—</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="table2fn1">
                <p><sup>a</sup>E: Young modulus.</p>
              </fn>
              <fn id="table2fn2">
                <p><sup>b</sup>ν: Poisson ratio. Where missing, the value of ν was assumed to be 0.45.</p>
              </fn>
              <fn id="table2fn3">
                <p><sup>c</sup>α: material exponent parameter.</p>
              </fn>
              <fn id="table2fn4">
                <p><sup>d</sup>μ: ground shear hyperelastic modulus.</p>
              </fn>
              <fn id="table2fn5">
                <p><sup>e</sup>D: compressibility constant.</p>
              </fn>
              <fn id="table2fn6">
                <p><sup>f</sup>DCM: degenerative cervical myelopathy.</p>
              </fn>
              <fn id="table2fn7">
                <p><sup>g</sup>Not available.</p>
              </fn>
              <fn id="table2fn8">
                <p><sup>h</sup>Values in italics are input based on the identity for isotropic materials, D=3(1-2ν)/(μ{1+ν}), and for linear elastic, μ=E/(2{1+ν}).</p>
              </fn>
              <fn id="table2fn9">
                <p><sup>i</sup>SCI: spinal cord injury.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
        </sec>
        <sec>
          <title>Pia</title>
          <p>Of the 26 FEA articles with defined pia, 14 (54%) used a linear elastic function, 9 (21%) did not report their method, and 2 (5%) used a hyperelastic Ogden variant function. The remaining study (1/26, 4%) used tabulated data from the study by Ichihara et al [<xref ref-type="bibr" rid="ref73">73</xref>].</p>
          <p>A total of 4 source articles were identified for the pia (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>), of which 2 (50%) were shortlisted as suitable [<xref ref-type="bibr" rid="ref75">75</xref>,<xref ref-type="bibr" rid="ref77">77</xref>]. The choice of material laws and the values of those who directly cited these shortlisted source articles are listed in <xref ref-type="table" rid="table3">Table 3</xref>. These equations have differences in how they represent the source article (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>). Of the FEA articles representing material properties with an equation, the study by Jannesar et al [<xref ref-type="bibr" rid="ref38">38</xref>] was selected as the most preferred.</p>
          <table-wrap position="float" id="table3">
            <label>Table 3</label>
            <caption>
              <p>Extracted material equations for the pia.</p>
            </caption>
            <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
              <col width="180"/>
              <col width="90"/>
              <col width="160"/>
              <col width="110"/>
              <col width="110"/>
              <col width="80"/>
              <col width="60"/>
              <col width="50"/>
              <col width="60"/>
              <col width="100"/>
              <thead>
                <tr valign="top">
                  <td>Study, year</td>
                  <td>Pathology</td>
                  <td>Reference</td>
                  <td>Law</td>
                  <td>Variant</td>
                  <td>E<sup>a</sup> (MPa)</td>
                  <td>ν<sup>b</sup></td>
                  <td>α<sup>c</sup></td>
                  <td>μ<sup>d</sup> (MPa)</td>
                  <td>D<sup>e</sup> (MPa<sup>−</sup><sup>1</sup>)</td>
                </tr>
              </thead>
              <tbody>
                <tr valign="top">
                  <td>Henao et al [<xref ref-type="bibr" rid="ref58">58</xref>,<xref ref-type="bibr" rid="ref59">59</xref>], 2017</td>
                  <td>Other</td>
                  <td>Tunturi [<xref ref-type="bibr" rid="ref75">75</xref>], 1978</td>
                  <td>Linear elastic</td>
                  <td>—<sup>f</sup></td>
                  <td>100</td>
                  <td>0.4</td>
                  <td>—</td>
                  <td>
                    <italic>35.71<sup>g</sup></italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Nishida et al [<xref ref-type="bibr" rid="ref91">91</xref>], 2016</td>
                  <td>DCM<sup>h</sup></td>
                  <td>Tunturi [<xref ref-type="bibr" rid="ref75">75</xref>], 1978</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Nishida et al [<xref ref-type="bibr" rid="ref54">54</xref>], 2015</td>
                  <td>DCM</td>
                  <td>Tunturi [<xref ref-type="bibr" rid="ref75">75</xref>], 1978</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Nishida et al [<xref ref-type="bibr" rid="ref55">55</xref>], 2014</td>
                  <td>DCM</td>
                  <td>Tunturi [<xref ref-type="bibr" rid="ref75">75</xref>], 1978</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Nishida et al [<xref ref-type="bibr" rid="ref22">22</xref>], 2012</td>
                  <td>DCM</td>
                  <td>Tunturi [<xref ref-type="bibr" rid="ref75">75</xref>], 1978</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Henao et al [<xref ref-type="bibr" rid="ref58">58</xref>], 2018</td>
                  <td>Other</td>
                  <td>Tunturi [<xref ref-type="bibr" rid="ref75">75</xref>], 1978</td>
                  <td>Linear elastic</td>
                  <td>—</td>
                  <td>100</td>
                  <td>0.4</td>
                  <td>—</td>
                  <td>
                    <italic>35.71</italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Kato et al [<xref ref-type="bibr" rid="ref56">56</xref>], 2010</td>
                  <td>DCM</td>
                  <td>Tunturi [<xref ref-type="bibr" rid="ref75">75</xref>], 1978</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Kato et al [<xref ref-type="bibr" rid="ref62">62</xref>], 2008</td>
                  <td>Other</td>
                  <td>Tunturi [<xref ref-type="bibr" rid="ref75">75</xref>], 1978</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Kato et al [<xref ref-type="bibr" rid="ref63">63</xref>], 2009</td>
                  <td>Other</td>
                  <td>Tunturi [<xref ref-type="bibr" rid="ref75">75</xref>], 1978</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Jannesar et al [<xref ref-type="bibr" rid="ref38">38</xref>], 2016<sup>i</sup></td>
                  <td>SCI</td>
                  <td>Kimpara et al [<xref ref-type="bibr" rid="ref77">77</xref>], 2006</td>
                  <td>Linear elastic</td>
                  <td>—</td>
                  <td>39.3</td>
                  <td>0.3</td>
                  <td>—</td>
                  <td>
                    <italic>15.12</italic>
                  </td>
                  <td>—</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="table3fn1">
                <p><sup>a</sup>E: Young modulus.</p>
              </fn>
              <fn id="table3fn2">
                <p><sup>b</sup>ν: Poisson ratio. Where missing, the value of ν was assumed to be 0.45.</p>
              </fn>
              <fn id="table3fn3">
                <p><sup>c</sup>α: material exponent parameter.</p>
              </fn>
              <fn id="table3fn4">
                <p><sup>d</sup>μ: ground shear hyperelastic modulus.</p>
              </fn>
              <fn id="table3fn5">
                <p><sup>e</sup>D: compressibility constant.</p>
              </fn>
              <fn id="table3fn6">
                <p><sup>f</sup>Not available.</p>
              </fn>
              <fn id="table3fn7">
                <p><sup>g</sup>Values in italics are input based on the identity for isotropic materials, D=3(1-2ν)/(μ{1+ν}), and for linear elastic, μ=E/(2{1+ν}).</p>
              </fn>
              <fn id="table3fn8">
                <p><sup>h</sup>DCM: degenerative cervical myelopathy.</p>
              </fn>
              <fn id="table3fn9">
                <p><sup>i</sup>The single preferred source of the authors based on modelling (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>).</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
        </sec>
        <sec>
          <title>Dura</title>
          <p>Of the 26 models with defined dura, 18 (69%) used a linear elastic function, 5 (19%) used a hyperelastic Ogden variant, and 3 (12%) did not report their method.</p>
          <p>Persson et al [<xref ref-type="bibr" rid="ref46">46</xref>] compared the performance of a linear and hyperelastic function, which is summarized in the following CSF section.</p>
          <p>A total of 9 source articles were referenced (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>), of which 4 (44%) were shortlisted [<xref ref-type="bibr" rid="ref78">78</xref>-<xref ref-type="bibr" rid="ref81">81</xref>]. The choice of material laws and values of those who directly cited these prioritized source articles are listed in <xref ref-type="table" rid="table4">Table 4</xref>. These equations have differences in how they represent the source article (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>). Of the FEA articles representing material properties with an equation, the study by Sparrey et al [<xref ref-type="bibr" rid="ref33">33</xref>] was selected as preferred.</p>
          <table-wrap position="float" id="table4">
            <label>Table 4</label>
            <caption>
              <p>Extracted material equations for the dura.</p>
            </caption>
            <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
              <col width="180"/>
              <col width="90"/>
              <col width="130"/>
              <col width="110"/>
              <col width="90"/>
              <col width="120"/>
              <col width="50"/>
              <col width="50"/>
              <col width="80"/>
              <col width="100"/>
              <thead>
                <tr valign="top">
                  <td>Study, year</td>
                  <td>Pathology</td>
                  <td>Reference</td>
                  <td>Law</td>
                  <td>Variant</td>
                  <td>E<sup>a</sup> (MPa)</td>
                  <td>ν<sup>b</sup></td>
                  <td>α<sup>c</sup></td>
                  <td>μ<sup>d</sup> (MPa)</td>
                  <td>D<sup>e</sup> (MPa<sup>−</sup><sup>1</sup>)</td>
                </tr>
              </thead>
              <tbody>
                <tr valign="top">
                  <td>Stoner et al [<xref ref-type="bibr" rid="ref20">20</xref>], 2020</td>
                  <td>DCM<sup>f</sup></td>
                  <td>Persson et al [<xref ref-type="bibr" rid="ref92">92</xref>], 2020</td>
                  <td>Linear Elastic</td>
                  <td>—<sup>g</sup></td>
                  <td>5</td>
                  <td>0.45</td>
                  <td>—</td>
                  <td>
                    <italic>1.72</italic>
                    <sup>h</sup>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref49">49</xref>], 2018</td>
                  <td>DCM</td>
                  <td>Persson et al [<xref ref-type="bibr" rid="ref92">92</xref>], 2020</td>
                  <td>Linear Elastic</td>
                  <td>—</td>
                  <td>80</td>
                  <td>0.49</td>
                  <td>—</td>
                  <td>
                    <italic>26.85</italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Henao et al [<xref ref-type="bibr" rid="ref58">58</xref>,<xref ref-type="bibr" rid="ref59">59</xref>], 2017</td>
                  <td>Other</td>
                  <td>Wilcox et al [<xref ref-type="bibr" rid="ref47">47</xref>], 2004</td>
                  <td>Linear Elastic</td>
                  <td>—</td>
                  <td>231</td>
                  <td>0.45</td>
                  <td>—</td>
                  <td>
                    <italic>79.66</italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref52">52</xref>], 2017</td>
                  <td>DCM</td>
                  <td>Persson et al [<xref ref-type="bibr" rid="ref92">92</xref>], 2020</td>
                  <td>Linear Elastic</td>
                  <td>—</td>
                  <td>80</td>
                  <td>0.49</td>
                  <td>—</td>
                  <td>
                    <italic>26.85</italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Sparrey et al [<xref ref-type="bibr" rid="ref33">33</xref>], 2016<sup>i</sup></td>
                  <td>SCI</td>
                  <td>Hong et al [<xref ref-type="bibr" rid="ref78">78</xref>], 2011 and Zarzur et al [<xref ref-type="bibr" rid="ref79">79</xref>], 1996</td>
                  <td>Hyper-elastic</td>
                  <td>Ogden,1st Order</td>
                  <td>—</td>
                  <td>0.45</td>
                  <td>16.2</td>
                  <td>1.205</td>
                  <td>0.172</td>
                </tr>
                <tr valign="top">
                  <td>Yan et al [<xref ref-type="bibr" rid="ref36">36</xref>], 2012</td>
                  <td>SCI</td>
                  <td>Wilcox et al [<xref ref-type="bibr" rid="ref47">47</xref>], 2004</td>
                  <td>Linear Elastic</td>
                  <td>—</td>
                  <td>142</td>
                  <td>0.45</td>
                  <td>—</td>
                  <td>
                    <italic>48.97</italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Henao et al [<xref ref-type="bibr" rid="ref58">58</xref>], 2018</td>
                  <td>Other</td>
                  <td>Wilcox et al [<xref ref-type="bibr" rid="ref47">47</xref>], 2004</td>
                  <td>Linear Elastic</td>
                  <td>—</td>
                  <td>231</td>
                  <td>0.45</td>
                  <td>—</td>
                  <td>
                    <italic>79.66</italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref39">39</xref>], 2016</td>
                  <td>SCI</td>
                  <td>Persson et al [<xref ref-type="bibr" rid="ref92">92</xref>], 2020</td>
                  <td>Linear Elastic</td>
                  <td>—</td>
                  <td>80</td>
                  <td>0.49</td>
                  <td>—</td>
                  <td>
                    <italic>26.85</italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref57">57</xref>], 2015</td>
                  <td>DCM</td>
                  <td>Persson et al [<xref ref-type="bibr" rid="ref92">92</xref>], 2020</td>
                  <td>Linear Elastic</td>
                  <td>—</td>
                  <td>80</td>
                  <td>0.49</td>
                  <td>—</td>
                  <td>
                    <italic>26.85</italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref57">57</xref>], 2015</td>
                  <td>SCI</td>
                  <td>Persson et al [<xref ref-type="bibr" rid="ref92">92</xref>], 2020</td>
                  <td>Linear Elastic</td>
                  <td>—</td>
                  <td>80</td>
                  <td>0.49</td>
                  <td>—</td>
                  <td>
                    <italic>26.85</italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Czyz et al [<xref ref-type="bibr" rid="ref42">42</xref>], 2008</td>
                  <td>SCI</td>
                  <td>Wilcox et al [<xref ref-type="bibr" rid="ref47">47</xref>], 2004</td>
                  <td>Linear Elastic</td>
                  <td>—</td>
                  <td>142</td>
                  <td>0.45</td>
                  <td>—</td>
                  <td>
                    <italic>48.97</italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Persson et al [<xref ref-type="bibr" rid="ref46">46</xref>], 2011</td>
                  <td>SCI</td>
                  <td>Persson et al [<xref ref-type="bibr" rid="ref92">92</xref>], 2020</td>
                  <td>Linear Elastic</td>
                  <td>—</td>
                  <td>80</td>
                  <td>0.49</td>
                  <td>—</td>
                  <td>
                    <italic>26.85</italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Wilcox et al [<xref ref-type="bibr" rid="ref47">47</xref>], 2004</td>
                  <td>SCI</td>
                  <td>Wilcox et al [<xref ref-type="bibr" rid="ref47">47</xref>], 2004</td>
                  <td>Anisotropic Elastic</td>
                  <td>—</td>
                  <td>Young modulus in the radial direction=142, Young modulus in the circumferential direction=142, Young modulus in the longitudinal direction=0.7</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                  <td>—</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="table4fn1">
                <p><sup>a</sup>E: Young modulus.</p>
              </fn>
              <fn id="table4fn2">
                <p><sup>b</sup>ν: Poisson ratio. Where missing, the value of ν was assumed to be 0.45.</p>
              </fn>
              <fn id="table4fn3">
                <p><sup>c</sup>α: material exponent parameter.</p>
              </fn>
              <fn id="table4fn4">
                <p><sup>d</sup>μ: ground shear hyperelastic modulus.</p>
              </fn>
              <fn id="table4fn5">
                <p><sup>e</sup>D: compressibility constant.</p>
              </fn>
              <fn id="table4fn6">
                <p><sup>f</sup>DCM: degenerative cervical myelopathy.</p>
              </fn>
              <fn id="table4fn7">
                <p><sup>g</sup>Not available.</p>
              </fn>
              <fn id="table4fn8">
                <p><sup>h</sup>Values in italics are input based on the identity for isotropic materials, D=3(1-2ν)/(μ{1+ν}), and for linear elastic, μ=E/(2{1+ν}).</p>
              </fn>
              <fn id="table4fn9">
                <p><sup>i</sup>The single preferred source of the authors based on modelling (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>).</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
        </sec>
        <sec>
          <title>Dentate Ligament</title>
          <p>Of the 13 FEA articles that included the dentate ligament, 12 (92%) used a linear elastic function and 1 (8%) used tabulated data. Typically, these were modeled using shell elements (6/13, 46%) with geometric properties, but 8% (1/13) used link elements and 15% (2/13) used spring elements.</p>
          <p>A total of 2 source articles were referenced (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>), of which both were shortlisted [<xref ref-type="bibr" rid="ref75">75</xref>,<xref ref-type="bibr" rid="ref82">82</xref>]. The choice of material laws and values of those who directly cited these prioritized source articles are listed in <xref ref-type="table" rid="table5">Table 5</xref>.</p>
          <table-wrap position="float" id="table5">
            <label>Table 5</label>
            <caption>
              <p>Extracted material equations for the dentate.</p>
            </caption>
            <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
              <col width="180"/>
              <col width="90"/>
              <col width="150"/>
              <col width="110"/>
              <col width="90"/>
              <col width="80"/>
              <col width="60"/>
              <col width="60"/>
              <col width="80"/>
              <col width="100"/>
              <thead>
                <tr valign="top">
                  <td>Study, year</td>
                  <td>Pathology</td>
                  <td>Reference</td>
                  <td>Law</td>
                  <td>Variant</td>
                  <td>E<sup>a</sup> (MPa)</td>
                  <td>ν<sup>b</sup></td>
                  <td>α<sup>c</sup></td>
                  <td>μ<sup>d</sup> (MPa)</td>
                  <td>D<sup>e</sup> (MPa<sup>−</sup><sup>1</sup>)</td>
                </tr>
              </thead>
              <tbody>
                <tr valign="top">
                  <td>Henao et al [<xref ref-type="bibr" rid="ref58">58</xref>,<xref ref-type="bibr" rid="ref59">59</xref>], 2017</td>
                  <td>Other</td>
                  <td>Tunturi [<xref ref-type="bibr" rid="ref75">75</xref>], 1978</td>
                  <td>Linear elastic</td>
                  <td>—<sup>f</sup></td>
                  <td>100</td>
                  <td>0.4</td>
                  <td>—</td>
                  <td>
                    <italic>35.7</italic>
                    <sup>g</sup>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Henao et al [<xref ref-type="bibr" rid="ref58">58</xref>], 2018</td>
                  <td>Other</td>
                  <td>Tunturi [<xref ref-type="bibr" rid="ref75">75</xref>], 1978</td>
                  <td>Linear elastic</td>
                  <td>—</td>
                  <td>100</td>
                  <td>0.4</td>
                  <td>—</td>
                  <td>
                    <italic>35.7</italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Greaves et al [<xref ref-type="bibr" rid="ref41">41</xref>], 2008</td>
                  <td>SCI<sup>h</sup></td>
                  <td>Tunturi [<xref ref-type="bibr" rid="ref75">75</xref>], 1978</td>
                  <td>Linear elastic</td>
                  <td>—</td>
                  <td>5.8</td>
                  <td>—</td>
                  <td>—</td>
                  <td>
                    <italic>2.0</italic>
                  </td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Czyz et al [<xref ref-type="bibr" rid="ref42">42</xref>], 2008</td>
                  <td>SCI</td>
                  <td>Tunturi [<xref ref-type="bibr" rid="ref75">75</xref>], 1978</td>
                  <td>Linear elastic</td>
                  <td>—</td>
                  <td>100</td>
                  <td>0.3</td>
                  <td>—</td>
                  <td>
                    <italic>38.5</italic>
                  </td>
                  <td>—</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="table5fn1">
                <p><sup>a</sup>E: Young modulus.</p>
              </fn>
              <fn id="table5fn2">
                <p><sup>b</sup>ν: Poisson ratio. Where missing, the value of ν was assumed to be 0.45.</p>
              </fn>
              <fn id="table5fn3">
                <p><sup>c</sup>α: material exponent parameter.</p>
              </fn>
              <fn id="table5fn4">
                <p><sup>d</sup>μ: ground shear hyperelastic modulus.</p>
              </fn>
              <fn id="table5fn5">
                <p><sup>e</sup>D: compressibility constant.</p>
              </fn>
              <fn id="table5fn6">
                <p><sup>f</sup>Not available.</p>
              </fn>
              <fn id="table5fn7">
                <p><sup>g</sup>Values in italics are input based on the identity for isotropic materials, D=3(1-2ν)/(μ{1+ν}), and for linear elastic, μ=E/(2{1+ν}).</p>
              </fn>
              <fn id="table5fn8">
                <p><sup>h</sup>SCI: spinal cord injury.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
        </sec>
        <sec>
          <title>Cerebrospinal Fluid</title>
          <p>Of the 17 models that included CSF, 8 (47%) modeled it as a Newtonian fluid. Alternatives included modeling CSF as a pressurized fluid cavity (1/17, 6%), modeling it as a polynomial equation of state (1/17, 6%), modeling it as smoothed particular hydrodynamics (1/17, 6%), using a hyperelastic Mooney-Rivlin model (3/17, 18%), or using a linear elastic equation (1/17, 6%).</p>
          <p>Persson et al [<xref ref-type="bibr" rid="ref46">46</xref>] and Jones et al [<xref ref-type="bibr" rid="ref93">93</xref>] specifically explored the implications of including a CSF cavity, with or without the dura. To measure cord deformation, Persson et al [<xref ref-type="bibr" rid="ref46">46</xref>] used an FEA model with reference to a transverse bovine impaction model of SCI, whereas Jones et al [<xref ref-type="bibr" rid="ref93">93</xref>] performed their own bovine and surrogate cord experiments. They observed that the presence of CSF reduced stress and strain (Persson et al [<xref ref-type="bibr" rid="ref46">46</xref>]) on the spinal cord and deformation (Jones et al [<xref ref-type="bibr" rid="ref93">93</xref>]) in the spinal cord. Persson et al [<xref ref-type="bibr" rid="ref46">46</xref>] demonstrated this was through a greater longitudinal distribution, particularly when the dura was included and modeled using a hyperelastic Ogden (as opposed to linear elastic) function. Furthermore, Persson et al [<xref ref-type="bibr" rid="ref46">46</xref>] observed that cord deformation occurred upon contact with the dura (before the CSF between the spinal cord and the dura was redistributed). Jones et al [<xref ref-type="bibr" rid="ref93">93</xref>] observed that the inclusion of the dura only changed behavior if CSF was also included.</p>
          <p>Furthermore, Arhiptsov and Marom [<xref ref-type="bibr" rid="ref31">31</xref>] explored CSF pressure, alongside the presence or absence of epidural fat, using a computational contusion model of SCI based on a thoracic burst fracture. Both CSF and epidural fat were modeled using smoothed particular hydrodynamics. In a model without epidural fat, spinal cord stress and strain increased with increasing CSF pressure. However, in the model with epidural fat, spinal cord stress and strain decreased with increasing CSF pressure.</p>
          <p>A total of 5 source articles were referenced (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>), of which 3 (60%) were shortlisted [<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref83">83</xref>,<xref ref-type="bibr" rid="ref84">84</xref>]. The choice of material laws and values of those who directly cited these prioritized source articles are listed in <xref ref-type="table" rid="table6">Table 6</xref>.</p>
          <table-wrap position="float" id="table6">
            <label>Table 6</label>
            <caption>
              <p>Extracted material equations for the cerebrospinal fluid.</p>
            </caption>
            <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
              <col width="220"/>
              <col width="100"/>
              <col width="220"/>
              <col width="200"/>
              <col width="130"/>
              <col width="130"/>
              <thead>
                <tr valign="top">
                  <td>Study, year</td>
                  <td>Pathology</td>
                  <td>Reference</td>
                  <td>Law</td>
                  <td>Viscosity (Pa/s)</td>
                  <td>Density (kg/m<sup>3</sup>)</td>
                </tr>
              </thead>
              <tbody>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref52">52</xref>], 2017</td>
                  <td>DCM<sup>a</sup></td>
                  <td>Bloomfield et al [<xref ref-type="bibr" rid="ref83">83</xref>], 1998</td>
                  <td>Newtonian Fluid</td>
                  <td>0.001</td>
                  <td>—<sup>b</sup></td>
                </tr>
                <tr valign="top">
                  <td>Arhiptsov [<xref ref-type="bibr" rid="ref31">31</xref>], 2021</td>
                  <td>SCI<sup>c</sup></td>
                  <td>Persson et al [<xref ref-type="bibr" rid="ref46">46</xref>], 2011</td>
                  <td>Polynomial Equation of State</td>
                  <td>—</td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref39">39</xref>], 2016</td>
                  <td>DCM</td>
                  <td>Bloomfield et al [<xref ref-type="bibr" rid="ref83">83</xref>], 1998, Brydon et al [<xref ref-type="bibr" rid="ref84">84</xref>], 1995</td>
                  <td>Newtonian Fluid</td>
                  <td>0.001</td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref39">39</xref>], 2016</td>
                  <td>SCI</td>
                  <td>Bloomfield et al [<xref ref-type="bibr" rid="ref83">83</xref>], 1998, Brydon et al [<xref ref-type="bibr" rid="ref84">84</xref>], 1995</td>
                  <td>Newtonian Fluid</td>
                  <td>0.001</td>
                  <td>1000</td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref57">57</xref>], 2015</td>
                  <td>DCM</td>
                  <td>Bloomfield et al [<xref ref-type="bibr" rid="ref83">83</xref>], 1998, Brydon et al [<xref ref-type="bibr" rid="ref84">84</xref>], 1995</td>
                  <td>Newtonian Fluid</td>
                  <td>0.001</td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref57">57</xref>], 2015</td>
                  <td>SCI</td>
                  <td>Bloomfield et al [<xref ref-type="bibr" rid="ref83">83</xref>], 1998, Brydon et al [<xref ref-type="bibr" rid="ref84">84</xref>], 1995</td>
                  <td>Newtonian Fluid</td>
                  <td>0.001</td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Persson et al [<xref ref-type="bibr" rid="ref46">46</xref>], 2011</td>
                  <td>SCI</td>
                  <td>Bloomfield et al [<xref ref-type="bibr" rid="ref83">83</xref>], 1998</td>
                  <td>Newtonian Fluid</td>
                  <td>0.001</td>
                  <td>—</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="table6fn1">
                <p><sup>a</sup>DCM: degenerative cervical myelopathy.</p>
              </fn>
              <fn id="table6fn2">
                <p><sup>b</sup>Not available.</p>
              </fn>
              <fn id="table6fn3">
                <p><sup>c</sup>SCI: spinal cord injury.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
        </sec>
        <sec>
          <title>Posterior Longitudinal Ligament and Ligamentum Flavum</title>
          <p>The analysis focused on the posterior longitudinal ligament and ligamentum flavum, given their specific involvement in the pathobiology of DCM. In all 6 instances included, they were included together and modeled in the same manner: using piecewise linear plasticity (2/6, 33%), linear elastic function (2/6, 33%), hyperelastic Ogden variant (1/6, 17%), or tabulated data (1/6, 17%).</p>
          <p>A total of 6 source articles were referenced (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>), of which 3 (50%) were shortlisted [<xref ref-type="bibr" rid="ref85">85</xref>-<xref ref-type="bibr" rid="ref87">87</xref>]. The choice of material laws and values of those who directly cited these prioritized source articles are listed in <xref ref-type="table" rid="table7">Tables 7</xref> and <xref ref-type="table" rid="table8">8</xref>.</p>
          <table-wrap position="float" id="table7">
            <label>Table 7</label>
            <caption>
              <p>Extracted material equations for the ligamentum flavum.</p>
            </caption>
            <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
              <col width="180"/>
              <col width="90"/>
              <col width="170"/>
              <col width="110"/>
              <col width="90"/>
              <col width="80"/>
              <col width="50"/>
              <col width="50"/>
              <col width="80"/>
              <col width="100"/>
              <thead>
                <tr valign="top">
                  <td>Study, year</td>
                  <td>Pathology</td>
                  <td>Reference</td>
                  <td>Law</td>
                  <td>Variant</td>
                  <td>E<sup>a</sup> (MPa)</td>
                  <td>ν<sup>b</sup></td>
                  <td>α<sup>c</sup></td>
                  <td>μ<sup>d</sup> (MPa)</td>
                  <td>D<sup>e</sup> (MPa<sup>−</sup><sup>1</sup>)</td>
                </tr>
              </thead>
              <tbody>
                <tr valign="top">
                  <td>Greaves et al [<xref ref-type="bibr" rid="ref41">41</xref>], 2008</td>
                  <td>SCI<sup>f</sup></td>
                  <td>Yoganandan et al 1989 and 2000 [<xref ref-type="bibr" rid="ref86">86</xref>,<xref ref-type="bibr" rid="ref87">87</xref>]</td>
                  <td>Linear elastic</td>
                  <td>—<sup>g</sup></td>
                  <td>3.8</td>
                  <td>—</td>
                  <td>—</td>
                  <td>
                    <italic>1.3</italic>
                    <sup>h</sup>
                  </td>
                  <td>—</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="table7fn1">
                <p><sup>a</sup>E: Young modulus.</p>
              </fn>
              <fn id="table7fn2">
                <p><sup>b</sup>ν: Poisson ratio. Where missing, the value of ν was assumed to be 0.45.</p>
              </fn>
              <fn id="table7fn3">
                <p><sup>c</sup>α: material exponent parameter.</p>
              </fn>
              <fn id="table7fn4">
                <p><sup>d</sup>μ: ground shear hyperelastic modulus.</p>
              </fn>
              <fn id="table7fn5">
                <p><sup>e</sup>D: compressibility constant.</p>
              </fn>
              <fn id="table7fn6">
                <p><sup>f</sup>SCI: spinal cord injury.</p>
              </fn>
              <fn id="table7fn7">
                <p><sup>g</sup>Not available.</p>
              </fn>
              <fn id="table7fn8">
                <p><sup>h</sup>Values in italics are input based on the identity for isotropic materials, D=3(1-2ν)/(μ{1+ν}), and for linear elastic, μ=E/(2{1+ν}).</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
          <table-wrap position="float" id="table8">
            <label>Table 8</label>
            <caption>
              <p>Extracted material equations for the posterior longitudinal ligament.</p>
            </caption>
            <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
              <col width="180"/>
              <col width="90"/>
              <col width="170"/>
              <col width="110"/>
              <col width="90"/>
              <col width="80"/>
              <col width="50"/>
              <col width="50"/>
              <col width="80"/>
              <col width="100"/>
              <thead>
                <tr valign="top">
                  <td>Study, year</td>
                  <td>Pathology</td>
                  <td>Reference</td>
                  <td>Law</td>
                  <td>Variant</td>
                  <td>E<sup>a</sup> (MPa)</td>
                  <td>ν<sup>b</sup></td>
                  <td>α<sup>c</sup></td>
                  <td>μ<sup>d</sup> (MPa)</td>
                  <td>D<sup>e</sup> (MPa<sup>−</sup><sup>1</sup>)</td>
                </tr>
              </thead>
              <tbody>
                <tr valign="top">
                  <td>Greaves et al [<xref ref-type="bibr" rid="ref41">41</xref>], 2008</td>
                  <td>SCI<sup>f</sup></td>
                  <td>Przybylski et al [<xref ref-type="bibr" rid="ref85">85</xref>], 1996 and Yoganandan 1989 and 2000 [<xref ref-type="bibr" rid="ref86">86</xref>,<xref ref-type="bibr" rid="ref87">87</xref>]</td>
                  <td>Linear elastic</td>
                  <td>—<sup>g</sup></td>
                  <td>35.7</td>
                  <td>—</td>
                  <td>—</td>
                  <td>
                    <italic>12.3</italic>
                    <sup>h</sup>
                  </td>
                  <td>—</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="table8fn1">
                <p><sup>a</sup>E: Young modulus.</p>
              </fn>
              <fn id="table8fn2">
                <p><sup>b</sup>ν: Poisson ratio. Where missing, the value of ν was assumed to be 0.45.</p>
              </fn>
              <fn id="table8fn3">
                <p><sup>c</sup>α: material exponent parameter.</p>
              </fn>
              <fn id="table8fn4">
                <p><sup>d</sup>μ: ground shear hyperelastic modulus.</p>
              </fn>
              <fn id="table8fn5">
                <p><sup>e</sup>D: compressibility constant.</p>
              </fn>
              <fn id="table8fn6">
                <p><sup>f</sup>SCI: spinal cord injury.</p>
              </fn>
              <fn id="table8fn7">
                <p><sup>g</sup>Not available.</p>
              </fn>
              <fn id="table8fn8">
                <p><sup>h</sup>Values in italics are input based on the identity for isotropic materials, D=3(1-2ν)/(μ{1+ν}), and for linear elastic, μ=E/(2{1+ν}).</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
        </sec>
        <sec>
          <title>Spinal Roots</title>
          <p>A total of 7 models included spinal nerve roots, of which 2 (29%) distinguished between the intradural and extradural components. These 2 models specifically explored the nature of C5 palsy in relation to surgery for DCM [<xref ref-type="bibr" rid="ref49">49</xref>,<xref ref-type="bibr" rid="ref57">57</xref>]. Nerve roots were all modeled with spring elements, either as a spring (5/7, 71%) or with a linear elastic equation (2/7, 29%).</p>
          <p>A total of 2 source articles of equivalent quality were referenced (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>) [<xref ref-type="bibr" rid="ref88">88</xref>,<xref ref-type="bibr" rid="ref89">89</xref>]. The choice of material laws and values of those who directly cited these prioritized source articles are listed in <xref ref-type="table" rid="table9">Table 9</xref>.</p>
          <table-wrap position="float" id="table9">
            <label>Table 9</label>
            <caption>
              <p>Extracted material equations for the nerve roots.</p>
            </caption>
            <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
              <col width="240"/>
              <col width="100"/>
              <col width="160"/>
              <col width="120"/>
              <col width="90"/>
              <col width="60"/>
              <col width="140"/>
              <col width="90"/>
              <thead>
                <tr valign="top">
                  <td>Study, year</td>
                  <td>Pathology</td>
                  <td>Reference</td>
                  <td>Law</td>
                  <td>E<sup>a</sup> (MPa)</td>
                  <td>ν<sup>b</sup></td>
                  <td>Spring constant</td>
                  <td>Mass (g)</td>
                </tr>
              </thead>
              <tbody>
                <tr valign="top">
                  <td>Lévy et al [<xref ref-type="bibr" rid="ref18">18</xref>], 2021</td>
                  <td>DCM<sup>c</sup></td>
                  <td>Kulkarni [<xref ref-type="bibr" rid="ref88">88</xref>], 2007</td>
                  <td>Spring</td>
                  <td>—<sup>d</sup></td>
                  <td>—</td>
                  <td>0.133</td>
                  <td>0.1</td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref49">49</xref>], 2018</td>
                  <td>DCM</td>
                  <td>Singh [<xref ref-type="bibr" rid="ref89">89</xref>], 2005</td>
                  <td>Linear Elastic</td>
                  <td>1.3</td>
                  <td>0.3</td>
                  <td>—</td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Henao et al [<xref ref-type="bibr" rid="ref58">58</xref>,<xref ref-type="bibr" rid="ref59">59</xref>], 2017</td>
                  <td>Other</td>
                  <td>Kulkarni [<xref ref-type="bibr" rid="ref88">88</xref>], 2007</td>
                  <td>Spring</td>
                  <td>—</td>
                  <td>—</td>
                  <td>0.133</td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref52">52</xref>], 2017</td>
                  <td>DCM</td>
                  <td>Singh [<xref ref-type="bibr" rid="ref89">89</xref>], 2005</td>
                  <td>Linear Elastic</td>
                  <td>1.3</td>
                  <td>0.3</td>
                  <td>—</td>
                  <td>—</td>
                </tr>
                <tr valign="top">
                  <td>Henao et al [<xref ref-type="bibr" rid="ref58">58</xref>], 2018</td>
                  <td>Other</td>
                  <td>Kulkarni [<xref ref-type="bibr" rid="ref88">88</xref>], 2007</td>
                  <td>Spring</td>
                  <td>—</td>
                  <td>—</td>
                  <td>0.133</td>
                  <td>—</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="table9fn1">
                <p><sup>a</sup>E: Young modulus.</p>
              </fn>
              <fn id="table9fn2">
                <p><sup>b</sup>ν: Poisson ratio; where missing, ν was assumed to be 0.45. For Kulkarni et al [<xref ref-type="bibr" rid="ref88">88</xref>], the unit is uncertain, with a range of different units referenced across its citations.</p>
              </fn>
              <fn id="table9fn3">
                <p><sup>c</sup>DCM: degenerative cervical myelopathy.</p>
              </fn>
              <fn id="table9fn4">
                <p><sup>d</sup>Not available.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
        </sec>
        <sec>
          <title>Other Elements</title>
          <p>Other elements included in some models were bone (14/41, 34%); intervertebral disks (IVDs; 13/41, 31%); and the remaining spinal ligaments, such as the anterior longitudinal or interspinous ligament.</p>
          <p>The bone was generally modeled as a rigid body (8/14, 57%). Of the 8 models, 3 (21%) subdivided the vertebrae into anatomical subcomponents (eg, body, laminae, and spinous process), and 5 (36%) distinguished between cortical and cancellous bone, of which 3 (60%) applied an equation just to the cortical bone (linear elastic in all cases) and 2 (40%) applied a Johnson-Cook or plastic kinematic equation. We found no eligible source articles using our search process.</p>
          <p>The IVD were modeled as a single entity in 54% (7/13) of the papers, typically as a rigid body (5/7, 71%) or using a linear elastic equation (2/7, 29%). Alternatively, they were modeled separately as nucleus pulposus and annulus fibrosus. Techniques for the nucleus pulposus included a Mooney-Rivlin model (3/6, 50%), Ogden second-order variant (1/6, 17%), and fluid elements (2/6, 33%). The annulus fibrosus included a Mooney-Rivlin model (2/6, 33%), Ogden second-order variant (1/6, 17%), Ogden third-order variant (1/6, 17%), and linear elastic equation (2/6, 33%).</p>
          <p>A total of 3 source articles were found for IVD, and 1 was shortlisted (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>) [<xref ref-type="bibr" rid="ref90">90</xref>]. The choice of material laws and values of those who directly cited these prioritized source articles are listed in <xref ref-type="table" rid="table10">Table 10</xref>.</p>
          <table-wrap position="float" id="table10">
            <label>Table 10</label>
            <caption>
              <p>Extracted material equations for the intervertebral disc.</p>
            </caption>
            <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
              <col width="180"/>
              <col width="90"/>
              <col width="170"/>
              <col width="110"/>
              <col width="90"/>
              <col width="80"/>
              <col width="50"/>
              <col width="50"/>
              <col width="80"/>
              <col width="100"/>
              <thead>
                <tr valign="top">
                  <td>Study, year</td>
                  <td>Pathology</td>
                  <td>Reference</td>
                  <td>Law</td>
                  <td>Variant</td>
                  <td>E<sup>a</sup> (MPa)</td>
                  <td>ν<sup>b</sup></td>
                  <td>α<sup>c</sup></td>
                  <td>μ<sup>d</sup> (MPa)</td>
                  <td>D<sup>e</sup> (MPa<sup>−</sup><sup>1</sup>)</td>
                </tr>
              </thead>
              <tbody>
                <tr valign="top">
                  <td>Greaves et al [<xref ref-type="bibr" rid="ref41">41</xref>], 2008</td>
                  <td>SCI<sup>f</sup></td>
                  <td>Spilker et al [<xref ref-type="bibr" rid="ref90">90</xref>], 1986</td>
                  <td>Linear elastic</td>
                  <td>—<sup>g</sup></td>
                  <td>3.4</td>
                  <td>—</td>
                  <td>—</td>
                  <td>
                    <italic>1.2</italic>
                    <sup>h</sup>
                  </td>
                  <td>—</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="table10fn1">
                <p><sup>a</sup>E: Young modulus.</p>
              </fn>
              <fn id="table10fn2">
                <p><sup>b</sup>ν: Poisson ratio. Where missing, the value of ν was assumed to be 0.45.</p>
              </fn>
              <fn id="table10fn3">
                <p><sup>c</sup>α: material exponent parameter.</p>
              </fn>
              <fn id="table10fn4">
                <p><sup>d</sup>μ: ground shear hyperelastic modulus.</p>
              </fn>
              <fn id="table10fn5">
                <p><sup>e</sup>D: compressibility constant.</p>
              </fn>
              <fn id="table10fn6">
                <p><sup>f</sup>SCI: spinal cord injury.</p>
              </fn>
              <fn id="table10fn7">
                <p><sup>g</sup>Not available.</p>
              </fn>
              <fn id="table10fn8">
                <p><sup>h</sup>Values in italics are input based on the identity for isotropic materials, D=3(1-2ν)/(μ{1+ν}), and for linear elastic, μ=E/(2{1+ν}).</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
        </sec>
      </sec>
      <sec>
        <title>Findings From the FEA Studies of DCM</title>
        <p>Of the DCM models, 60% (9/15) specifically focused on ossification of the posterior longitudinal ligament (OPLL), a specific subtype of DCM.</p>
        <sec>
          <title>Stress and Static Cord Compression</title>
          <p>A total of 8 models explored the relationship between the amount of static spinal cord compression and spinal cord stress. Kato et al [<xref ref-type="bibr" rid="ref56">56</xref>] and Kim et al [<xref ref-type="bibr" rid="ref21">21</xref>] used parametric models of the spinal cord to explore the implications of OPLL (anterior) compression at 2 adjacent vertebrae. The model was constrained posteriorly, reflecting the lamina. They found that the stress increased with increasing cord compression, with an apparent exponential relationship. Minimal stress was detected at &#60;40% but dramatically increased at ≥50%. This relationship was replicated by Nishida et al [<xref ref-type="bibr" rid="ref91">91</xref>] using posterior compression, by Liang et al [<xref ref-type="bibr" rid="ref48">48</xref>] simulating a disk prolapse, and in a multisegmental model of OPLL by Khuyagbaatar et al [<xref ref-type="bibr" rid="ref52">52</xref>,<xref ref-type="bibr" rid="ref57">57</xref>]. Furthermore, it was replicated in cervical spondylosis by Levy et al [<xref ref-type="bibr" rid="ref18">18</xref>] (<xref rid="figure3" ref-type="fig">Figure 3</xref> [<xref ref-type="bibr" rid="ref18">18</xref>,<xref ref-type="bibr" rid="ref21">21</xref>,<xref ref-type="bibr" rid="ref52">52</xref>,<xref ref-type="bibr" rid="ref57">57</xref>]).</p>
          <p>Maximal stress was observed in the gray matter and, to a lesser extent, in the lateral and posterior funiculus. Nishida et al [<xref ref-type="bibr" rid="ref91">91</xref>] observed differences in the stress distribution at low compression rates depending on the spinal cord level related to differing morphology; however, beyond a compression rate of 30%, this was consistent (<xref rid="figure4" ref-type="fig">Figure 4</xref>).</p>
          <p>Okazaki et al [<xref ref-type="bibr" rid="ref50">50</xref>] explored the implications of spinal cord aging using a parametric model of the spinal cord. The model was given white and gray matter properties based on a young or aged bovine spinal cord specimen. They observed that stress increased under a low amount of anterior compression in the aged spinal cord and was more widely distributed throughout the gray matter and white matter. In contrast, the gray matter was unaffected in the young specimen.</p>
          <fig id="figure3" position="float">
            <label>Figure 3</label>
            <caption>
              <p>Spinal cord compression and spinal cord stress in degenerative cervical myelopathy models. For models tabulating the von Mises stress at different measures of static compression or canal stenosis (n=4) [<xref ref-type="bibr" rid="ref18">18</xref>,<xref ref-type="bibr" rid="ref21">21</xref>,<xref ref-type="bibr" rid="ref52">52</xref>,<xref ref-type="bibr" rid="ref57">57</xref>], the values were plotted on a line graph with a line of best fit representing the average value (blue).</p>
            </caption>
            <graphic xlink:href="biomedeng_v9i1e48146_fig3.png" alt-version="no" mimetype="image" position="float" xlink:type="simple"/>
          </fig>
          <fig id="figure4" position="float">
            <label>Figure 4</label>
            <caption>
              <p>Spinal cord compression and location of spinal cord stress in degenerative cervical myelopathy models. The spinal cord was partitioned, per hemicord, as gray matter and anterior, anterolateral, posterolateral, and posterior white matter. For each study, reporting the cross-sectional distribution of Von Mises stress (n=12) and the location of stress that fell within the top 30% of measured stress was noted. These frequencies were aggregated by compression pattern and displayed for (A) anterior diffuse and static, (B) anterior focal and static, and (C) circumferential and dynamic distribution and location of stress as relative proportions.</p>
            </caption>
            <graphic xlink:href="biomedeng_v9i1e48146_fig4.png" alt-version="no" mimetype="image" position="float" xlink:type="simple"/>
          </fig>
        </sec>
        <sec>
          <title>Stress and Dynamic Cord Compression</title>
          <p>Nishida et al [<xref ref-type="bibr" rid="ref22">22</xref>] used a parametric model to explore the implications of ligamentum flavum buckling in neck extension in the context of cervical stenosis. For this, the spinal cord was restricted posteriorly by the ligamentum flavum and then anteriorly, either by a central curvature (representing a disk prolapse) or a flat lateral or flat cross-sectional constraint (representing the ligament). The amount of ligamentum flavum buckling was measured using a kinematic MRI. Spinal cord stress was observed in all scenarios and was maximal using the flat cross-sectional constraint.</p>
          <p>Later, Nishida et al [<xref ref-type="bibr" rid="ref54">54</xref>] used a parametric model of OPLL to demonstrate that while dynamic and static compression alone could stress the spinal cord, they could also act together, although it was unclear whether this was additive or multiplicative. In dynamic compression alone, stress was more restricted to gray matter.</p>
        </sec>
        <sec>
          <title>Stress and Shape of Cord Compression</title>
          <p>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref57">57</xref>] and Kim et al [<xref ref-type="bibr" rid="ref21">21</xref>] did not identify any difference in OPLL shape or type with respect to observed spinal cord stress. Furthermore, in the study by Nishida et al [<xref ref-type="bibr" rid="ref22">22</xref>], the distribution of stress was broadly comparable across the three scenarios affecting the gray matter and anterior and posterolateral aspects of the white matter tracts. In unilateral compression only, the ipsilateral gray matter was affected. Levy et al [<xref ref-type="bibr" rid="ref18">18</xref>] explored gradually increasing anterior diffuse (broad-based disk), anterior lateral, and circumferential compression using a static multilevel model. Different phenotypes of stress were observed, including peak stress, point of onset, and rate of increase. The highest stress was observed with an anterior diffuse or circumferential compression (<xref rid="figure4" ref-type="fig">Figure 4</xref>).</p>
        </sec>
        <sec>
          <title>Stress and Surgical Decompression</title>
          <p>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref39">39</xref>] used a multisegmental model to explore the implications of hemilaminectomy, laminectomy, and laminoplasty on spinal cord stress following a 1-, 2-, 3-, or 4-level posterior decompression for continuous OPLL. Stress remained elevated following hemilaminectomy but was low and equivalent between laminectomy and laminoplasty. The postoperative deformity was not modeled.</p>
          <p>Nishida et al [<xref ref-type="bibr" rid="ref55">55</xref>] used a parametric model to explore the implications of alignment following posterior decompression for OPLL. They demonstrated that although stress decreased significantly following decompression, it slightly increased in the anterior funiculus, increasing in the gray matter and posterolateral funiculi with progressive deformity. They subsequently replicated this in a separate analysis [<xref ref-type="bibr" rid="ref51">51</xref>], demonstrating that kyphosis and increased mobility after decompression would elevate the observed stress.</p>
          <p>Khuyagbaatar et al [<xref ref-type="bibr" rid="ref49">49</xref>,<xref ref-type="bibr" rid="ref52">52</xref>] explored the effects of laminectomy and laminoplasty, respectively, for the treatment of OPLL using a multisegmental static compression model. They demonstrated that all procedures reduced spinal cord stress significantly (&#62;90%), whether in lordotic (K Line positive) or kyphotic deformity (K Line negative) [<xref ref-type="bibr" rid="ref94">94</xref>]. However, stress was elevated within the exiting C5 nerve root following laminectomy if there was a kyphotic deformity and lateral-type OPLL following laminoplasty. In both instances, the amount of nerve root stress was related to the amount of anterior compression.</p>
          <p>Stoner et al [<xref ref-type="bibr" rid="ref20">20</xref>] used a multisegmental dynamic model (C2-T1) to explore the implications of multilevel C4-7 cervical spondylosis (anterior disk prolapses and osteophyte formation) treated with C4-7 anterior cervical discectomy and fusion (ACDF), laminoplasty, or ACDF with laminectomy. Notably, all procedures caused stress to increase at adjacent levels above those of healthy controls. However, a stand-alone ACDF caused increased stress within the spinal cord at C3 to a level above that of the preoperative DCM model in flexion.</p>
          <p>Where possible, these were aggregated, demonstrating that the spinal cord tolerated significant compression before stress increased exponentially (<xref rid="figure3" ref-type="fig">Figure 3</xref> [<xref ref-type="bibr" rid="ref18">18</xref>,<xref ref-type="bibr" rid="ref21">21</xref>,<xref ref-type="bibr" rid="ref52">52</xref>,<xref ref-type="bibr" rid="ref57">57</xref>]). Aggregating the distributions of stress observed across studies, based on the nature of compression, demonstrated differing stress distributions (<xref rid="figure4" ref-type="fig">Figure 4</xref>). For static and diffuse anterior compression, the bilateral posterior white matter and gray matter were the most affected. For static and focal compression, the anterior white matter and, to a lesser extent, the gray matter were most affected. This was observed bilaterally despite a focal or lateral element. For circumferential compression in a dynamic model, the bilateral gray matter and posterior white matter were the most affected.</p>
        </sec>
        <sec>
          <title>Stress and Tissue Injury</title>
          <p>Notably, although differential patterns of stress were observed throughout these DCM models, the levels remained relatively low (&#60;0.5 MPa). DCM FEA models did not explore the relationship between the observed stress and tissue injury.</p>
        </sec>
      </sec>
    </sec>
    <sec sec-type="discussion">
      <title>Discussion</title>
      <sec>
        <title>Overview</title>
        <p>FEA is a promising technique used in DCM, although there remain uncertainties regarding the ideal approach and its clinical interpretation. This review highlights the numerous decisions investigators must make when performing FEA, which can affect findings and underpin the need for a systematic approach, as applied in this study. On the basis of current evidence, we have shortlisted our preferred material property choices for a DCM model and conclude that a distinction between gray and white matter is preferable.</p>
      </sec>
      <sec>
        <title>Principal Findings and Comparison to Prior Work</title>
        <p>A total of 15 studies were identified applying FEA to investigate DCM. The insights from these studies broadly align with the current evidence base. First, the spinal cord can tolerate some compression. This is in keeping with clinical practice, where asymptomatic spinal cord compression is far more common [<xref ref-type="bibr" rid="ref3">3</xref>], and the amount of cord compression is a poor surrogate for disease severity or progression [<xref ref-type="bibr" rid="ref1">1</xref>]. Second, the movement of the subaxial cervical spine can augment the stress on the spinal cord. This is in keeping with clinical practice, including the concept of dynamic injury and the proposed role of flexion/extension MRI or electrophysiology [<xref ref-type="bibr" rid="ref95">95</xref>-<xref ref-type="bibr" rid="ref98">98</xref>]. Finally, it demonstrated the significant effectiveness of decompression surgery, regardless of the technique, and the comparatively minor gains of using one technique over the other. This is in keeping with clinical practice, where high-quality comparisons of anterior versus posterior surgery are equivalent, and currently, there is no strong evidence that routine stabilization (eg, instrumented fusion vs laminoplasty vs laminectomy or ACDF vs ACDF with a plate) is required [<xref ref-type="bibr" rid="ref99">99</xref>-<xref ref-type="bibr" rid="ref102">102</xref>], all pointing toward the need for a personalized surgical approach [<xref ref-type="bibr" rid="ref15">15</xref>].</p>
        <p>Furthermore, although more nuanced findings were proposed by the identified FEA studies and this would require in vivo corroboration, the application of FEA in DCM appears well founded overall. More widely, it also seems potentially valuable and timely. The pathobiology of DCM is poorly understood, with its investigation being among the top 10 global research priorities [<xref ref-type="bibr" rid="ref1">1</xref>]. Current preclinical models have many limitations. For example, common recent models use an expandable polymer inserted behind the spinal cord and within the canal to cause cervical myelopathy. Therefore, this does not model anterior compression, nor does it truly represent a chronic injury mechanism. Furthermore, in clinical practice, clinical decisions are based on imperfect tools [<xref ref-type="bibr" rid="ref103">103</xref>]. For example, structural MRI in a supine position defines the nature of degenerative changes but not if, where, or how an SCI occurs. FEA could change this, particularly given the parallel advances in the automatic segmentation of MRI [<xref ref-type="bibr" rid="ref12">12</xref>].</p>
        <p>Furthermore, while this review highlights that FEA is a versatile technique, investigators must make many decisions regarding how it is applied. These decisions can alter the findings and, therefore, must be carefully considered. At this stage, there seem to be only a few pervasive insights. First, it seems prudent to model the white matter and gray matter separately. Ichihara et al [<xref ref-type="bibr" rid="ref73">73</xref>] demonstrated that these structures have differing material properties, and how they are defined alters the observed stress and strain. Furthermore, these structures age differently, as shown by Ozawa et al [<xref ref-type="bibr" rid="ref76">76</xref>]. Histological studies of DCM have shown differing disease features among the white matter and gray matter, with the gray matter being the focus of more significant cellular changes [<xref ref-type="bibr" rid="ref9">9</xref>]. Moreover, aging is an important factor in DCM, associated with greater disease severity, a greater rate of progression, and poorer response to treatment [<xref ref-type="bibr" rid="ref104">104</xref>]. There are also early indicators that accelerating aging is a pathological process [<xref ref-type="bibr" rid="ref1">1</xref>]. Therefore, the observation that the gray matter was unaffected in the younger spinal cord specimen is noteworthy [<xref ref-type="bibr" rid="ref34">34</xref>,<xref ref-type="bibr" rid="ref45">45</xref>,<xref ref-type="bibr" rid="ref50">50</xref>].</p>
        <p>Second, while some models have chosen to use linear elastic equations, time-independent hyperelastic models more closely reflected the known material properties of the spinal cord. These, or simply tabulated data, were generally adopted by DCM studies and supported by a single study that evaluated different approaches [<xref ref-type="bibr" rid="ref38">38</xref>]. Conceptually, taking a more faithful approach to modeling the spinal cord material properties is likely to be more applicable to DCM and its etiology, as contrasted with traumatic SCI, spinal cord stress may be below the limits for tissue injury (eg, asymptomatic spinal cord compression), and above (eg, DCM). It is worth noting that none of these approaches considers the impact of repetitive injuries, and it is likely that time dependence in modeling is relevant [<xref ref-type="bibr" rid="ref1">1</xref>]. Given the timeline of DCM pathogenesis (years), this is likely beyond the normal material scales.</p>
        <p>Finally, similar to DCM, as the stresses involved are well below the elastic limit of the bone, the vertebrae can be modeled simply as rigid bodies. The critical aspect for bones is instead the way that their geometry and movement affect the loading on the soft tissues.</p>
        <p>However, there remain many uncertainties for further evaluation. These include the role of spinal cord oscillation, the appropriateness of the reference material properties for DCM, and the relationship between the measured stress and tissue injury. First, no studies specifically consider spinal cord oscillations [<xref ref-type="bibr" rid="ref105">105</xref>]. The spinal cord oscillates cranio-caudally with heart rate. Recent imaging studies have indicated that this increased in the context of symptomatic stenosis, the nature of which may correlate with clinical measures of disease severity [<xref ref-type="bibr" rid="ref106">106</xref>,<xref ref-type="bibr" rid="ref107">107</xref>]. Spinal cord oscillation would likely result in a shear force on the spinal cord.</p>
        <p>Second, it is uncertain how applicable the material properties are to DCM. Most elements are based on young healthy tissue references. In contrast, the ligaments and disks, for example, in DCM, are often degenerated and calcified, and, as aforementioned, the structure of the spinal cord is also recognized to change with age.</p>
        <p>However, most importantly, none of these studies have specifically explored how the measured stress is related to tissue injury. Bridging this gap is critical, not only to fully confirm the appropriateness of FEA for DCM but also to guide its clinical interpretation [<xref ref-type="bibr" rid="ref108">108</xref>]. All biological systems will have some baseline stress or strain; therefore, establishing disease thresholds will be critical to its development. The parallel development of in vivo techniques to measure tissue injury can complement this, for example, microstructural MRI and the less developed but promising serum and CSF biomarkers; however, this requires further prospective study.</p>
      </sec>
      <sec>
        <title>Limitations</title>
        <p>This study has some limitations. First, the search strategy focused on FEA models of the spinal cord and used citations to identify the source articles for all anatomical elements. Consequently, relevant source articles on the behavior of anatomical elements may have been missed. This is more likely for elements that were further removed from the spinal cord, such as the IVD, and experiments published more recently. This was a pragmatic decision based on the fact that existing investigators would likely have the best perspective on the literature, that this is a small research field, and that detailed biomechanical data on elements such as the IVD were unlikely to be so relevant. Consistent decisions across different research groups and findings across source articles would endorse this. Furthermore, due to the nature of our synthesis, we were unable to update our search. Although this may result in the omission of newer FEA articles, we believe that our review provides a useful approach for future investigators aiming to use FEA in DCM. Second, the methods used to shortlist source articles represent a framework we developed for the purpose of building a DCM FEA model. Again, the popularity of the shortlisted articles across research groups provides some external validation, but it is possible that different investigators would reach different conclusions. For this reason, all source articles are listed in <xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>, with their respective direct object identifiers. Third, this review aggregates data from a range of different experimental approaches and aims. Therefore, the analysis is largely qualitative, adhering to the SWiM guidelines [<xref ref-type="bibr" rid="ref26">26</xref>]. Consequently, some conclusions, such as the relationship between the nature of spinal cord compression and stress distribution, remain tentative.</p>
      </sec>
      <sec>
        <title>Conclusions</title>
        <p>FEA has significant potential to help unlock uncertainties around the pathophysiology of DCM and inform clinical care. Currently, the application of FEA to DCM remains in its infancy. This review has adopted an intensive and iterative approach to help future investigators use FEA in DCM, including the aggregation of experimental data reporting on material properties and how they have been interpreted thus far. While single recommendations have been made, they have their limitations. The choice of material properties will influence the model performance, and investigators should consider their decisions carefully, particularly as new evidence emerges. More broadly, the methodology used in this review may be relevant to future updates and other clinical FEA initiatives when selecting material properties.</p>
      </sec>
    </sec>
  </body>
  <back>
    <app-group>
      <supplementary-material id="app1">
        <label>Multimedia Appendix 1</label>
        <p>PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) checklist.</p>
        <media xlink:href="biomedeng_v9i1e48146_app1.docx" xlink:title="DOCX File , 108 KB"/>
      </supplementary-material>
      <supplementary-material id="app2">
        <label>Multimedia Appendix 2</label>
        <p>Search strategy.</p>
        <media xlink:href="biomedeng_v9i1e48146_app2.docx" xlink:title="DOCX File , 13 KB"/>
      </supplementary-material>
      <supplementary-material id="app3">
        <label>Multimedia Appendix 3</label>
        <p>The quality assessment tool developed by the authors.</p>
        <media xlink:href="biomedeng_v9i1e48146_app3.docx" xlink:title="DOCX File , 13 KB"/>
      </supplementary-material>
      <supplementary-material id="app4">
        <label>Multimedia Appendix 4</label>
        <p>Comparison of modeling decisions.</p>
        <media xlink:href="biomedeng_v9i1e48146_app4.docx" xlink:title="DOCX File , 274 KB"/>
      </supplementary-material>
      <supplementary-material id="app5">
        <label>Multimedia Appendix 5</label>
        <p>Comparison of chosen equation and reference material property study.</p>
        <media xlink:href="biomedeng_v9i1e48146_app5.docx" xlink:title="DOCX File , 936 KB"/>
      </supplementary-material>
      <supplementary-material id="app6">
        <label>Multimedia Appendix 6</label>
        <p>Material properties of other anatomical elements.</p>
        <media xlink:href="biomedeng_v9i1e48146_app6.docx" xlink:title="DOCX File , 1052 KB"/>
      </supplementary-material>
      <supplementary-material id="app7">
        <label>Multimedia Appendix 7</label>
        <p>Interactive network files.</p>
        <media xlink:href="biomedeng_v9i1e48146_app7.zip" xlink:title="ZIP File  (Zip Archive), 561 KB"/>
      </supplementary-material>
      <supplementary-material id="app8">
        <label>Multimedia Appendix 8</label>
        <p>Higher-resolution version of <xref rid="figure2" ref-type="fig">Figure 2</xref>.</p>
        <media xlink:href="biomedeng_v9i1e48146_app8.png" xlink:title="PNG File , 5013 KB"/>
      </supplementary-material>
    </app-group>
    <glossary>
      <title>Abbreviations</title>
      <def-list>
        <def-item>
          <term id="abb1">ACDF</term>
          <def>
            <p>anterior cervical discectomy and fusion</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb2">CSF</term>
          <def>
            <p>cerebrospinal fluid</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb3">DCM</term>
          <def>
            <p>degenerative cervical myelopathy</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb4">FEA</term>
          <def>
            <p>finite element analysis</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb5">IVD</term>
          <def>
            <p>intervertebral disk</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb6">MRI</term>
          <def>
            <p>magnetic resonance imaging</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb7">OPLL</term>
          <def>
            <p>ossification of the posterior longitudinal ligament</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb8">PRISMA-ScR</term>
          <def>
            <p>Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb9">SCI</term>
          <def>
            <p>spinal cord injury</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb10">SWiM</term>
          <def>
            <p>Synthesis Without Meta-Analysis</p>
          </def>
        </def-item>
      </def-list>
    </glossary>
    <ack>
      <p>This study aligns with the AO Spine Research Objectives and Common Data Elements for Degenerative Cervical Myelopathy (RECODE-DCM) James Lind Alliance top research priorities, selected by people living and working with degenerative cervical myelopathy. This includes “biological basis,” and, to a lesser extent, “individualizing surgery” and “imaging and electrophysiology.” VN is supported by an NIHR Rosetrees Advanced Trust Fellowship. BMD was supported by a National Institute for Health Research Clinical Doctoral Research Fellowship. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, Rosetrees Trust or the Department of Health and Social Care. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.</p>
    </ack>
    <notes>
      <sec>
        <title>Data Availability</title>
        <p>The data sets generated during and analyzed during this study are available from the corresponding author on reasonable request.</p>
      </sec>
    </notes>
    <fn-group>
      <fn fn-type="con">
        <p>BMD designed the study, developed the search strategy, conducted the searches, screened the retrieved papers, extracted relevant information, and drafted the manuscript. SS contributed to paper screening and data extraction. ARF contributed to the writing of the subsequent drafts of this paper. VJFN and MPFS contributed throughout the project, starting from conceptualization to study design, search strategy development, and editing subsequent drafts of the paper.</p>
      </fn>
      <fn fn-type="conflict">
        <p>None declared.</p>
      </fn>
    </fn-group>
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