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Open Access Publications from the University of California

Scholarly Works (10 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2021)

The overall goal of the dissertation research is to provide insights into the fundamental structure-composition-function relationship in lumbar intervertebral discs. The research develops and validates a novel multiscale multiphasic structure-based framework for modeling the intervertebral disc and soft fiber-reinforced biological tissues with accuracy, robustness, and translatability, which helps elucidate important stress-bearing mechanisms in both healthy and degenerated disc tissues. The proposed modeling framework and the subsequent model outcomes could have broad scientific and clinical implications related to the development of in vitro testing protocols with improved effectiveness, robustness, and clinical relevance, the design of novel tissue-engineered structures, and the evaluation of subfailure and failure behaviors in healthy and pathological tissues. Ultimately, the hope is that the modeling framework presented and validated in the current work can serve as a foundation for developing and validating future intervertebral disc and fiber-reinforced biological tissue models with patient-specific geometries, morphologies, and pathologies, and the resulting models can be used to improve clinical outcomes of low back pain treatments and, in turn, contribute to the broad effort of addressing this global health concern.

This dissertation comprises a series of separate, but related finite element modeling studies that focus on the development, validation, and application of the proposed models. The goals of these studies are to obtain an accurate, robust, and translatable finite element modeling framework to investigate multiscale and multiphasic disc mechanics, including, but are not limited to, joint stiffness and the stress-bearing contribution of the interstitial fluid at the joint scale, annulus fibrosus (AF) uniaxial tensile mechanics at the tissue scale, and AF stress transmission mechanisms and fiber-matrix interactions at the subtissue scale, under various physiologically relevant boundary and loading conditions in both healthy and degenerated tissues.

The primary results highlighted the accuracy, robustness, and translatability of the modeling framework proposed in the dissertation. Model predictions closely matched experimental measurements across the joint, tissue, and subtissue scales under various boundary and loading conditions with different specimen geometries. Joint- and tissue-scale model outcomes emphasized the significant stress-bearing role of the disc interstitial fluid content (i.e., the tissue water content accounted for up to ~60% of the joint’s stress-bearing capability in healthy discs), highlighting the necessity of multiphasic modeling. Tissue- and subtissue-scale model outcomes provided comprehensive explanations for the hard-to-interpret geometry dependence widely observed in AF tensile mechanics research and directly measured AF fiber stretch that were impossible to characterize during in situ and in vitro testing, highlighting the benefits of directly describing subtissue-level structures using the multiscale structure-based modeling approach.

Model outcomes also highlighted the importance of designing study-specific testing protocols based on individual research objectives. Particularly, physiologically representative specimen geometry, boundary condition, and loading condition should be applied if the measurements are intended to be interpreted in the context of clinical relevance, and vice versa. For example, in this dissertation, model outcomes across the joint, tissue, and subtissue scales helped identify the non-physiologically representative instantaneous center of rotation as a main issue for current herniation testing protocols, highlighting that the finite element models proposed in the current research could serve as a powerful yet effective complementary tool when designing testing protocols for resource- and time-intensive experiments.

In conclusion, a novel multiscale multiphasic structure-based framework is developed and validated for modeling the intervertebral disc; the resulting finite element models are proven accurate, robust, and translatable. The proposed modeling framework provides an effective tool for directly investigating the multiscale disc mechanics, especially at the subtissue scale, with degeneration, disease, and injury. The modeling framework with the subsequent model outcomes has the potential to help lay the foundation for future experimental-computational combined research that aims to comprehend disc and soft tissue failure mechanisms, providing a powerful tool that complements clinical diagnoses and treatments for low back pain.

    Cover page: A Novel Multiscale Multiphasic Structure-Based Modeling Framework for the Intervertebral Disc
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2024)
    Lumbar intervertebral disc herniation, as a leading cause of low back pain, productivity loss, and disability, is a common musculoskeletal disorder that results in significant socioeconomic burdens. Despite extensive clinical and basic scientific research efforts, herniation etiopathogenesis, particularly its initiation and progression, is not well understood. Understanding herniation etiopathogenesis is essential for developing effective preventive measures and therapeutic interventions. Thus, this review seeks to provide a thorough overview of the advances in herniation-oriented research, with a discussion on ongoing challenges and potential future directions for clinical, translational, and basic scientific investigations to facilitate innovative interdisciplinary research aimed at understanding herniation etiopathogenesis. Specifically, risk factors for herniation are identified and summarized, including familial predisposition, obesity, diabetes mellitus, smoking tobacco, selected cardiovascular diseases, disc degeneration, and occupational risks. Basic scientific experimental and computational research that aims to understand the link between excessive mechanical load, catabolic tissue remodeling due to inflammation or insufficient nutrient supply, and herniation, are also reviewed. Potential future directions to address the current challenges in herniation-oriented research are explored by combining known progressive development in existing research techniques with ongoing technological advances. More research on the relationship between occupational risk factors and herniation, as well as the relationship between degeneration and herniation, is needed to develop preventive measures for working-age individuals. Notably, researchers should explore using or modifying existing degeneration animal models to study herniation etiopathogenesis, as such models may allow for a better understanding of how to prevent mild-to-moderately degenerated discs from herniating.
      Cover page: Understanding the etiopathogenesis of lumbar intervertebral disc herniation: From clinical evidence to basic scientific research.
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2021)
      A comprehensive understanding of multiscale and multiphasic intervertebral disc mechanics is crucial for designing advanced tissue engineered structures aiming to recapitulate native tissue behavior. The bovine caudal disc is a commonly used human disc analog due to its availability, large disc height and area, and similarities in biochemical and mechanical properties to the human disc. Because of challenges in directly measuring subtissue-level mechanics, such as in situ fiber mechanics, finite element models have been widely employed in spinal biomechanics research. However, many previous models use homogenization theory and describe each model element as a homogenized combination of fibers and the extrafibrillar matrix while ignoring the role of water content or osmotic behavior. Thus, these models are limited in their ability in investigating subtissue-level mechanics and stress-bearing mechanisms through fluid pressure. The objective of this study was to develop and validate a structure-based bovine caudal disc model, and to evaluate multiscale and multiphasic intervertebral disc mechanics under different loading conditions and with degeneration. The structure-based model was developed based on native disc structure, where fibers and matrix in the annulus fibrosus were described as distinct materials occupying separate volumes. Model parameters were directly obtained from experimental studies without calibration. Under the multiscale validation framework, the model was validated across the joint-, tissue-, and subtissue-levels. Our model accurately predicted multiscale disc responses for 15 of 16 cases, emphasizing the accuracy of the model, as well as the effectiveness and robustness of the multiscale structure-based modeling-validation framework. The model also demonstrated the rim as a weak link for disc failure, highlighting the importance of keeping the cartilage endplate intact when evaluating disc failure mechanisms in vitro. Importantly, results from this study elucidated important fluid-based load-bearing mechanisms and fiber-matrix interactions that are important for understanding disease progression and regeneration in intervertebral discs. In conclusion, the methods presented in this study can be used in conjunction with experimental work to simultaneously investigate disc joint-, tissue-, and subtissue-level mechanics with degeneration, disease, and injury.
        Cover page: A Robust Multiscale and Multiphasic Structure-Based Modeling Framework for the Intervertebral Disc
        • Article
        • Peer Reviewed
        UC Berkeley Previously Published Works (2017)
        Tears in the annulus fibrosus (AF) of the intervertebral disk can result in disk herniation and progressive degeneration. Understanding AF failure mechanics is important as research moves toward developing biological repair strategies for herniated disks. Unfortunately, failure mechanics of fiber-reinforced tissues, particularly tissues with fibers oriented off-axis from the applied load, is not well understood, partly due to the high variability in reported mechanical properties and a lack of standard techniques ensuring repeatable failure behavior. Therefore, the objective of this study was to investigate the effectiveness of midlength (ML) notch geometries in producing repeatable and consistent tissue failure within the gauge region of AF mechanical test specimens. Finite element models (FEMs) representing several notch geometries were created to predict the location of bulk tissue failure using a local strain-based criterion. FEM results were validated by experimentally testing a subset of the modeled specimen geometries. Mechanical testing data agreed with model predictions (∼90% agreement), validating the model's predictive power. Two of the modified dog-bone geometries ("half" and "quarter") effectively ensured tissue failure at the ML for specimens oriented along the circumferential-radial and circumferential-axial directions. The variance of measured mechanical properties was significantly lower for notched samples that failed at the ML, suggesting that ML notch geometries result in more consistent and reliable data. In addition, the approach developed in this study provides a framework for evaluating failure properties of other fiber-reinforced tissues, such as tendons and meniscus.
          Cover page: A Novel Method for Repeatable Failure Testing of Annulus Fibrosus
          • Article
          • Peer Reviewed
          UC Berkeley Previously Published Works (2020)
          In many fiber-reinforced tissues, collagen fibers are embedded within a glycosaminoglycan-rich extrafibrillar matrix. Knowledge of the structure-function relationship between the sub-tissue properties and bulk tissue mechanics is important for understanding tissue failure mechanics and developing biological repair strategies. Difficulties in directly measuring sub-tissue properties led to a growing interest in employing finite element modeling approaches. However, most models are homogeneous and are therefore not sufficient for investigating multiscale tissue mechanics, such as stress distributions between sub-tissue structures. To address this limitation, we developed a structure-based model informed by the native annulus fibrosus structure, where fibers and the matrix were described as distinct materials occupying separate volumes. A multiscale framework was applied such that the model was calibrated at the sub-tissue scale using single-lamellar uniaxial mechanical test data, while validated at the bulk scale by predicting tissue multiaxial mechanics for uniaxial tension, biaxial tension, and simple shear (13 cases). Structure-based model validation results were compared to experimental observations and homogeneous models. While homogeneous models only accurately predicted bulk tissue mechanics for one case, structure-based models accurately predicted bulk tissue mechanics for 12 of 13 cases, demonstrating accuracy and robustness. Additionally, six of eight structure-based model parameters were directly linked to tissue physical properties, further broadening its future applicability. In conclusion, the structure-based model provides a powerful multiscale modeling approach for simultaneously investigating the structure-function relationship at the sub-tissue and bulk tissue scale, which is important for studying multiscale tissue mechanics with degeneration, disease, or injury.
            Cover page: Multiscale composite model of fiber-reinforced tissues with direct representation of sub-tissue properties
            • Article
            • Peer Reviewed
            UC Berkeley Previously Published Works (2022)
            The intervertebral disc is a complex structure that experiences multiaxial stresses regularly. Disc failure through herniation is a common cause of lower back pain, which causes reduced mobility and debilitating pain, resulting in heavy socioeconomic burdens. Unfortunately, herniation etiology is not well understood, partially due to challenges in replicating herniation in vitro. Previous studies suggest that flexion elevated risks of herniation. Thus, the objective of this study was to use a multiscale and multiphasic finite element model to evaluate the risk of failure under torque- or muscle-driven flexion. Models were developed to represent torque-driven flexion with the instantaneous center of rotation (ICR) located on the disc, and the more physiologically representative muscle-driven flexion with the ICR located anterior of the disc. Model predictions highlighted disparate disc mechanics regarding bulk deformation, stress-bearing mechanisms, and intradiscal stress-strain distributions. Specifically, failure was predicted to initiate at the bone-disc boundary under torque-driven flexion, which may explain why endplate junction failure, instead of herniation, has been the more common failure mode observed in vitro. By contrast, failure was predicted to initiate in the posterolateral annulus fibrosus under muscle-driven flexion, resulting in consistent herniation. Our findings also suggested that muscle-driven flexion combined with axial compression could be sufficient for provoking herniation in vitro and in silico. In conclusion, this study provided a computational framework for designing in vitro testing protocols that can advance the assessment of disc failure behavior and the performance of engineered disc implants.
              Cover page: Torque- and Muscle-Driven Flexion Induce Disparate Risks of In Vitro Herniation: A Multiscale and Multiphasic Structure-Based Finite Element Study.
              • Article
              • Peer Reviewed
              UC Berkeley Previously Published Works (2023)
              Growing clinical evidence suggests a correlation between diabetes and more frequent and severe intervertebral disc failure, partially attributed to accelerated advanced glycation end-products (AGE) accumulation in the annulus fibrosus (AF) through non-enzymatic glycation. However, in vitro glycation (i.e., crosslinking) reportedly improved AF uniaxial tensile mechanical properties, contradicting clinical observations. Thus, this study used a combined experimental-computational approach to evaluate the effect of AGEs on anisotropic AF tensile mechanics, applying finite element models (FEMs) to complement experimental testing and examine difficult-to-measure subtissue-level mechanics. Methylglyoxal-based treatments were applied to induce three physiologically relevant AGE levels in vitro. Models incorporated crosslinks by adapting our previously validated structure-based FEM framework. Experimental results showed that a threefold increase in AGE content resulted in a ∼55% increase in AF circumferential-radial tensile modulus and failure stress and a 40% increase in radial failure stress. Failure strain was unaffected by non-enzymatic glycation. Adapted FEMs accurately predicted experimental AF mechanics with glycation. Model predictions showed that glycation increased stresses in the extrafibrillar matrix under physiologic deformations, which may increase tissue mechanical failure or trigger catabolic remodeling, providing insight into the relationship between AGE accumulation and increased tissue failure. Our findings also added to the existing literature regarding crosslinking structures, indicating that AGEs had a greater effect along the fiber direction, while interlamellar radial crosslinks were improbable in the AF. In summary, the combined approach presented a powerful tool for examining multiscale structure-function relationships with disease progression in fiber-reinforced soft tissues, which is essential for developing effective therapeutic measures. STATEMENT OF SIGNIFICANCE: Increasing clinical evidence correlates diabetes with premature intervertebral disc failure, likely due to advanced glycation end-products (AGE) accumulation in the annulus fibrosus (AF). However, in vitro glycation reportedly increases AF tensile stiffness and toughness, contradicting clinical observations. Using a combined experimental-computational approach, our work shows that increases in AF bulk tensile mechanical properties with glycation are achieved at the risk of exposing the extrafibrillar matrix to increased stresses under physiologic deformations, which may increase tissue mechanical failure or trigger catabolic remodeling. Computational results indicate that crosslinks along the fiber direction account for 90% of the increased tissue stiffness with glycation, adding to the existing literature. These findings provide insight into the multiscale structure-function relationship between AGE accumulation and tissue failure.
                Cover page: Non-enzymatic glycation increases the failure risk of annulus fibrosus by predisposing the extrafibrillar matrix to greater stressesCreative Commons 'BY' version 4.0 license
                • Article
                • Peer Reviewed
                UC Berkeley Previously Published Works (2019)
                Bovine caudal discs have been widely used in spine research due to their increased availability, large size, and mechanical and biochemical properties that are comparable to healthy human discs. However, despite their extensive use, the radial variations in bovine disc composition have not yet been rigorously quantified with high spatial resolution. Previous studies were limited to qualitative analyses or provided limited spatial resolution in biochemical properties. Thus, the main objective of this study was to provide quantitative measurements of biochemical composition with higher spatial resolution than previous studies that employed traditional biochemical techniques. Specifically, traditional biochemical analyses were used to measure water, sulfated glycosaminoglycan, collagen, and DNA contents. Gravimetric water content was compared to data obtained through Raman spectroscopy and differential scanning calorimetry. Additionally, spatial distribution of lipids in the discs collagen network was visualized and quantified, for the first time, using multi-modal second harmonic generation (SHG) and Coherent anti-Stokes Raman (CARS) microscopy. Some heterogeneity was observed in the nucleus pulposus, where the water content and water-to-protein ratio of the inner nucleus were greater than the outer nucleus. In contrast, the bovine annulus fibrosus exhibited a more heterogeneous distribution of biochemical properties. Comparable results between orthohydroxyproline assay and SHG imaging highlight the potential benefit of using SHG microscopy as a less destructive method for measuring collagen content, particularly when relative changes are of interest. CARS images showed that lipid deposits were distributed equally throughout the disc and appeared either as individual droplets or as clusters of small droplets. In conclusion, this study provided a more comprehensive assessment of spatial variations in biochemical composition of the bovine caudal disc.
                  Cover page: Radial variation in biochemical composition of the bovine caudal intervertebral disc.
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2024)
                  High-resolution peripheral quantitative computed tomography (HR-pQCT) has emerged as a powerful imaging technique for characterizing bone microarchitecture in the human peripheral skeleton. The second-generation HR-pQCT scanner provides improved spatial resolution and a shorter scan time. However, the transition from the first-generation (XCTI) to second-generation HR-pQCT scanners (XCTII) poses challenges for longitudinal studies, multi-center trials, and comparison to historical data. Cross-calibration, an established approach for determining relationships between measurements obtained from different devices, can bridge this gap and enable the utilization and comparison of legacy data. The goal of this study was to establish cross-calibration equations to estimate XCTII measurements from XCTI data, using both the standard and Laplace-Hamming (LH) binarization approaches. Thirty-six volunteers (26-85 yr) were recruited and their radii and tibiae were scanned on both XCTI and XCTII scanners. XCTI images were analyzed using the manufacturer's standard protocol. XCTII images were analyzed twice: using the manufacturer's standard protocol and the LH segmentation approach previously developed and validated by our team. Linear regression analysis was used to establish cross-calibration equations. Results demonstrated strong correlations between XCTI and XCTII density and geometry outcomes. For most microstructural outcomes, although there were considerable differences in absolute values, correlations between measurements obtained from different scanners were strong, allowing for accurate cross-calibration estimations. For some microstructural outcomes with a higher sensitivity to spatial resolution (eg, trabecular thickness, cortical pore diameter), XCTII standard protocol resulted in poor correlations between the scanners, while our LH approach improved these correlations and decreased the difference in absolute values and the proportional bias for other measurements. For these reasons and due to the improved accuracy of our LH approach compared with the standard approach, as established in our previous study, we propose that investigators should use the LH approach for analyzing XCTII scans, particularly when comparing to XCTI data.
                    Cover page: HR-pQCT cross-calibration using standard vs. Laplace-Hamming binarization approachCreative Commons 'BY' version 4.0 license
                    • Article
                    • Peer Reviewed
                    UC Berkeley Previously Published Works (2019)
                    Bovine caudal discs have been widely used in spine research due to their increased availability, large size, and mechanical and biochemical properties that are comparable to healthy human discs. However, despite their extensive use, the radial variations in bovine disc composition have not yet been rigorously quantified with high spatial resolution. Previous studies were limited to qualitative analyses or provided limited spatial resolution in biochemical properties. Thus, the main objective of this study was to provide quantitative measurements of biochemical composition with higher spatial resolution than previous studies that employed traditional biochemical techniques. Specifically, traditional biochemical analyses were used to measure water, sulfated glycosaminoglycan, collagen, and DNA contents. Gravimetric water content was compared to data obtained through Raman spectroscopy and differential scanning calorimetry. Additionally, spatial distribution of lipids in the disc's collagen network was visualized and quantified, for the first time, using multi-modal second harmonic generation (SHG) and Coherent anti-Stokes Raman (CARS) microscopy. Some heterogeneity was observed in the nucleus pulposus, where the water content and water-to-protein ratio of the inner nucleus were greater than the outer nucleus. In contrast, the bovine annulus fibrosus exhibited a more heterogeneous distribution of biochemical properties. Comparable results between orthohydroxyproline assay and SHG imaging highlight the potential benefit of using SHG microscopy as a less destructive method for measuring collagen content, particularly when relative changes are of interest. CARS images showed that lipid deposits were distributed equally throughout the disc and appeared either as individual droplets or as clusters of small droplets. In conclusion, this study provided a more comprehensive assessment of spatial variations in biochemical composition of the bovine caudal disc.
                      Cover page: Radial variation in biochemical composition of the bovine caudal intervertebral disc
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