Jonathon H. Yoder

Noninvasive Quantification of Human Nucleus Pulposus Pressure with Use of T1ρ-Weighted Magnetic Resonance Imaging

BACKGROUND Early diagnosis is a challenge in the treatment of degenerative disc disease. A noninvasive biomarker detecting functional mechanics of the disc is needed. T1rho-weighted imaging, a spin-lock magnetic resonance imaging technique, has shown promise for meeting this need in in vivo studies demonstrating the clinical feasibility of evaluating both intervertebral discs and articular cartilage. The objectives of the present study were (1) to quantitatively determine the relationship between T1rho relaxation time and measures of nucleus pulposus mechanics, and (2) to evaluate whether the quantitative relationship of T1rho relaxation time with the degenerative grade and glycosaminoglycan content extend to more severe degeneration. It was hypothesized that the isometric swelling pressure and compressive modulus would be directly correlated with the T1rho relaxation time and the apparent permeability would be inversely correlated with the T1rho relaxation time. METHODS Eight cadaver human lumbar spines were imaged to measure T1rho relaxation times. The nucleus pulposus tissue from the L1 disc through the S1 disc was tested in confined compression to determine the swelling pressure, compressive modulus, and permeability. The glycosaminoglycan and water contents were measured in adjacent tissue. Linear regression analyses were performed to examine the correlation between the T1rho relaxation time and the other measured variables. Mechanical properties and biochemical content were evaluated for differences associated with degeneration. RESULTS A positive linear correlation was observed between the T1rho relaxation time on the images of the nucleus pulposus and the swelling pressure (r = 0.59), glycosaminoglycan content per dry weight (r = 0.69), glycosaminoglycan per wet weight (r = 0.49), and water content (r = 0.53). No significant correlations were observed between the T1rho relaxation time and the modulus or permeability. Similarly, the T1rho relaxation time, swelling pressure, glycosaminoglycan content per dry weight, and water content were significantly altered with degeneration, whereas the modulus and permeability were not. CONCLUSIONS T1rho-weighted magnetic resonance imaging has a strong potential as a quantitative biomarker of the mechanical function of the nucleus pulposus and of disc degeneration.

T1ρ magnetic resonance imaging and discography pressure as novel biomarkers for disc degeneration and low back pain.

Study Design. Prospective magnetic resonance imaging (MRI) study of patients low back pain (LBP) requiring discography as part of their routine clinical diagnoses and asymptomatic age-matched volunteers. Objective. To determine whether T1&rgr; MRI and discography opening pressure (OP) are quantitative biomarkers of disc degeneration in LBP patients and in asymptomatic volunteers. Summary of Background Data. Disc degenerative disease, a common cause of LBP, is related to the patients prognosis and serves as a target for therapeutic interventions. However, there are few quantitative measures in the clinical setting. Discography OP and T1&rgr; MRI are potential biomarkers of disc degenerative disease related to biochemical composition of the intervertebral disc. Methods. The institutional review board approved all experiments, and informed consent was provided by each subject. Patients being treated for LBP (n = 17; 68 levels; mean age, 44 ± 6 years; and range, 30–53) and control subjects (n = 11; 44 levels; mean age, 43 ± 17 years; and range, 22–76) underwent T1&rgr; and T2 MRI on a Siemens 3T Tim Trio clinical scanner (Siemens Medical Solutions, Malvern, PA). The LBP patients also received multilevel provocative discography before their MRI. OP was recorded as the pressure when fluid first enters the nucleus of the intervertebral disc. Results. T1&rgr; was significantly lower in the painful discs (55.3 ± 3.0 ms, mean ± SE) from control (92.0 ± 4.9 ms, P < 0.001) and nonpainful discs (83.6 ± 3.2 ms, P < 0.001). Mean OP for the painful discs (11.8 ± 1.0 psi, mean ± SE) was significantly lower than that for nonpainful discs (19.1 ± 0.7 psi, P < 0.001). Both T1&rgr; and OP correlated moderately with Pfirrmann degenerative grade. Receiver-operating-characteristic area under the curve was 0.91 for T1&rgr; MRI and 0.84 for OP for predicting painful discs. Conclusion. T1&rgr; and OP are quantitative measures of degeneration that are consistent across both control subjects and LBP patients. A significant and strong correlation exists between T1&rgr; values and in vivo OP measurements obtained by discography in LBP patients.

Human L3L4 intervertebral disc mean 3D shape, modes of variation, and their relationship to degeneration.

Intervertebral disc mechanics are affected by both disc shape and disc degeneration, which in turn each affect the other; disc mechanics additionally have a role in the etiology of disc degeneration. Finite element analysis (FEA) is a favored tool to investigate these relationships, but limited data for intervertebral disc 3D shape has forced the use of simplified or single-subject geometries, with the effect of inter-individual shape variation investigated only in specialized studies. Similarly, most data on disc shape variation with degeneration is based on 2D mid-sagittal images, which incompletely define 3D shape changes. Therefore, the objective of this study was to quantify inter-individual disc shape variation in 3D, classify this variation into independently-occurring modes using a statistical shape model, and identify correlations between disc shape and degeneration. Three-dimensional disc shapes were obtained from MRI of 13 human male cadaver L3L4 discs. An average disc shape and four major modes of shape variation (representing 90% of the variance) were identified. The first mode represented disc axial area and was significantly correlated to degeneration (R(2)=0.44), indicating larger axial area in degenerate discs. Disc height variation occurred in three distinct modes, each also involving non-height variation. The statistical shape model provides an average L3L4 disc shape for FEA that is fully defined in 3D, and makes it convenient to generate a set of shapes with which to represent aggregate inter-individual variation. Degeneration grade-specific shapes can also be generated. To facilitate application, the model is included in this paper׳s supplemental content.

Effect of orientation and targeted extracellular matrix degradation on the shear mechanical properties of the annulus fibrosus.

The intervertebral disc experiences combinations of compression, torsion, and bending that subject the disc substructures, particularly the annulus fibrosus (AF), to multidirectional loads and deformations. Combined tensile and shear loading is a particularly important loading paradigm, as compressive loads place the AF in circumferential hoop tension, and spine torsion or bending induces AF shear. Yet the anisotropy of AF mechanical properties in shear, as well as important structure-function mechanisms governing this response, are not well-understood. The objective of this study, therefore, was to investigate the effects of tissue orientation and enzymatic degradation of glycosaminoglycan (GAG) and elastin on AF shear mechanical properties. Significant anisotropy was found: the circumferential shear modulus, Gθz, was an order of magnitude greater than the radial shear modulus, Grθ. In the circumferential direction, prestrain significantly increased the shear modulus, suggesting an important role for collagen fiber stretch in shear properties for this orientation. While not significant and highly variable, ChABC treatment to remove GAG increased the circumferential shear modulus compared to PBS control (p=0.15). Together with the established literature for tensile loading of fiber-reinforced GAG-rich tissues, the trends for changes in shear modulus with ChABC treatment reflect complex, structure-function relationships between GAG and collagen that potentially occur over several hierarchical scales. Elastase digestion did not significantly affect shear modulus with respect to PBS control; further contributing to the notion that circumferential shear modulus is dominated by collagen fiber stretch. The results of this study highlight the complexity of the structure-function relationships that govern the mechanical response of the AF in radial and circumferential shear, and provide new and more accurate data for the validation of material models and tissue-engineered disc replacements.

Nonlinear and anisotropic tensile properties of graft materials used in soft tissue applications.

BACKGROUND The mechanical properties of extracellular matrix grafts that are intended to augment or replace soft tissues should be comparable to the native tissue. Such grafts are often used in fiber-reinforced tissue applications that undergo multi-axial loading and therefore knowledge of the anisotropic and nonlinear properties are needed, including the moduli and Poissons ratio in two orthogonal directions within the plane of the graft. The objective of this study was to measure the tensile mechanical properties of several marketed grafts: Alloderm, Restore, CuffPatch, and OrthADAPT. METHODS The degree of anisotropy and non-linearity within each graft was evaluated from uniaxial tensile tests and compared to their native tissue. FINDINGS The Alloderm graft was anisotropic in both the toe- and linear-region of the stress-strain response, was highly nonlinear, and generally had low properties. The Restore and CuffPatch grafts had similar stress-strain responses, were largely isotropic, had a linear-region modulus of 18MPa, and were nonlinear. OrthADAPT was anisotropic in the linear-region (131 MPA vs 47MPa in the toe-region) and was highly nonlinear. The Poisson ratio for all grafts was between 0.4 and 0.7, except for the parallel orientation of Restore which was greater than 1.0. INTERPRETATION Having an informed understanding of how the available grafts perform mechanically will allow for better assessment by the physician for which graft to apply depending upon its application.

Internal Three-Dimensional Strains in Human Intervertebral Discs Under Axial Compression Quantified Noninvasively by Magnetic Resonance Imaging and Image Registration

Study objectives were to develop, validate, and apply a method to measure three-dimensional (3D) internal strains in intact human discs under axial compression. A custom-built loading device applied compression and permitted load-relaxation outside of the magnet while also maintaining compression and hydration during imaging. Strain was measured through registration of 300 μm isotropic resolution images. Excellent registration accuracy was achieved, with 94% and 65% overlap of disc volume and lamellae compared to manual segmentation, and an average Hausdorff, a measure of distance error, of 0.03 and 0.12 mm for disc volume and lamellae boundaries, respectively. Strain maps enabled qualitative visualization and quantitative regional annulus fibrosus (AF) strain analysis. Axial and circumferential strains were highest in the lateral AF and lowest in the anterior and posterior AF. Radial strains were lowest in the lateral AF, but highly variable. Overall, this study provided new methods that will be valuable in the design and evaluation surgical procedures and therapeutic interventions.

Novel human intervertebral disc strain template to quantify regional three-dimensional strains in a population and compare to internal strains predicted by a finite element model

Tissue strain is an important indicator of mechanical function, but is difficult to noninvasively measure in the intervertebral disc. The objective of this study was to generate a disc strain template, a 3D average of disc strain, of a group of human L4–L5 discs loaded in axial compression. To do so, magnetic resonance images of uncompressed discs were used to create an average disc shape. Next, the strain tensors were calculated pixel‐wise by using a previously developed registration algorithm. Individual disc strain tensor components were then transformed to the template space and averaged to create the disc strain template. The strain template reduced individual variability while highlighting group trends. For example, higher axial and circumferential strains were present in the lateral and posterolateral regions of the disc, which may lead to annular tears. This quantification of group‐level trends in local 3D strain is a significant step forward in the study of disc biomechanics. These trends were compared to a finite element model that had been previously validated against the disc‐level mechanical response. Depending on the strain component, 81–99% of the regions within the finite element model had calculated strains within one standard deviation of the template strain results. The template creation technique provides a new measurement technique useful for a wide range of studies, including more complex loading conditions, the effect of disc pathologies and degeneration, damage mechanisms, and design and evaluation of treatments.

Quantification of intervertebral disc cartilaginous endplate morphology using MRI

Introduction: The cartilaginous endplate (CEP) is a thin layer of hyaline cartilage which functions as a mechanical barrier between the nucleus pulposus and the vertebral endplate and as a gateway for nutrient transport to the intervertebral disc. To date, the geometry of the CEP has not been well defined. This study visualizes the three-dimensional morphology of the CEP and quantifies CEP thickness via a semi-automatic analysis technique. Methods: Human lumbar motion segments (n=24) were imaged using an optimized 3D FLASH sequence. MRI data were evaluated in the axial and mid-sagittal imaging planes for CEP area, circumference, anterior-posterior width, lateral width, and thickness. CEP thickness was evaluated at five anterior-posterior locations. Results: There was no significant difference in CEP circumference, area, A-P width, or lateral width with respect to superior/inferior location (p>0.7) or disc level (p>0.6) except between L1L2 and L4L5 (p 0.5). Discussion: This study demonstrates the potential for MRI FLASH imaging coupled with automatic geometric quantification in evaluating the CEP as a potential contributor in the degenerative cascade.

Annulus Fibrosus Shear Properties Are Consistent With Motion Segment Mechanics When Fibers Are Loaded

The annulus fibrosus (AF) is a highly organized structure made up of concentric lamellae of fibers embedded in a hydrated extrafibrillar matrix; the collagen fibers are oriented at alternating angles in each lamella. The AF undergoes multidirectional loading through combinations of compression, bending, torsion and shear of the motion segment. The composition and structure of the AF leads to mechanical stress-strain nonlinearity and anisotropy. Previous tissue-based studies of shear have tested the AF tissue under compressive simple shear and torsion, producing shear modulus on the order of 0.06–0.4 MPa [1, 2]. However, structural testing and mathematical models of the IVD have reported the shear modulus to be between 3–20 MPa [3–6]. We hypothesize that when the fibers of the AF are loaded the shear modulus will be on the same order as structural tests and mathematical models of the IVD. The objectives of this study are to measure the shear mechanical properties of the bovine outer AF and compare the regional variances between anterior and posterior AF.© 2009 ASME

A model for intervertebral disc shape variation in a population including the effect of degeneration

The 3D shape of the intervertebral disc (IVD) is modeled in this work from a population of samples. Heretofore, 3D models of the disc have been created from individual samples only. L3/L4 discs were segmented from 14 magnetic resonance images. The mean shape was calculated using a signed distance function representation, and principal components analysis was used to re-express the residual variability with an orthonormal basis. The first basis vector, which represents lateral bulging of the disc, expresses the majority of the populations shape variation. This vector was also significantly correlated with Pfirrmann grade (p<0.01), a measure of disc degeneration. The IVD shape model can thus be used to generate an average IVD shape for the population, as well as shapes for specific degenerative grades.