James C. Iatridis

Degeneration affects the anisotropic and nonlinear behaviors of human anulus fibrosus in compression

Axial and radial specimens of non-degenerate and degenerate human anulus fibrosus (AF) were tested in confined compression to test the hypothesis that degeneration significantly affects the compressive properties of AF. Due to the highly oriented structure of AF, a secondary objective was to investigate anisotropic behaviors of AF in compression. Uniaxial swelling and stress relaxation experiments were performed on site-matched samples of anulus from the anterior outer region of L2-3 intervertebral discs. The experimental stress-relaxation behavior was modeled using the finite deformation biphasic theory and a finite-difference approximation scheme. Significant effects of degeneration but not orientation were detected for the reference stress offset, sigma(offset), and parameters describing the compressive stiffness (i.e. reference aggregate modulus, H(A0), and nonlinear stiffening coefficient, beta). Average values were 0.13+/-0.06 and 0.05+/-0.05 MPa for sigma(offset), 0.56+/-0.21 and 1.10+/-0.53 MPa for H(A0) and 2.13+/-1.48 and 0.44+/-0.61 for beta for all normal and degenerate specimens, respectively. No significant effect of degeneration or orientation were detected for either of the parameters describing the strain-dependent permeability (i.e. reference permeability, k0 and strain-dependent permeability coefficient, M) with average values for all specimens of 0.20+/-0.10 x 10(-15) m4/N-s and 1.18+/-1.30 for k0 and M, respectively. The loss of sigma(offset) was compensated with an elastic stiffening and change in the shape of the equilibrium stress-strain curve with H(A0) for degenerate tissues almost twice that of normal tissues and beta less than one sixth. The increase in reference elastic modulus with degeneration is likely related to an increase in tissue density resulting from the loss of water content. The significant effects of degeneration reported in this study suggested a shift in load carriage from fluid pressurization and swelling pressure to deformation of the solid matrix of the AF. The results also suggest that the highly organized and layered network of the anulus fibrosus, which gives rise to significant anisotropic effects in tension, does not play a major role in contributing to the magnitude of compressive stiffness or the mechanisms of fluid flow of the anulus in the confined compression configuration.

Compression-induced changes in intervertebral disc properties in a rat tail model.

STUDY DESIGN An Ilizarov-type apparatus was applied to the tails of rats to assess the influence of immobilization, chronically applied compression, and sham intervention on intervertebral discs of mature rats. OBJECTIVES To test the hypothesis that chronically applied compressive forces and immobilization cause changes in the biomechanical behavior and biochemical composition of rat tail intervertebral discs. SUMMARY OF BACKGROUND DATA Mechanical factors are associated with degenerative disc disease and low back pain, yet there have been few controlled studies in which the effects of compressive forces on the structure and function of the disc have been isolated. METHODS The tails of 16 Sprague-Dawley rats were instrumented with an Ilizarov-type apparatus. Animals were separated into sham, immobilization, and compression groups based on the mechanical conditions imposed. In vivo biomechanical measurements of disc thickness, angular laxity, and axial and angular compliance were made at 14-day intervals during the course of the 56-day experiment, after which discs were harvested for measurement of water, proteoglycan, and collagen contents. RESULTS Application of pins and rings alone (sham group) resulted in relatively small changes of in vivo biomechanical behavior. Immobilization resulted in decreased disc thickness, axial compliance, and angular laxity. Chronically applied compression had effects similar to those of immobilization alone but induced those changes earlier and in larger magnitudes. Application of external compressive forces also caused an increase in proteoglycan content of the intervertebral discs. CONCLUSIONS The well-controlled loading environment applied to the discs in this model provides a means of isolating the influence of joint-loading conditions on the response of the intervertebral disc. Results indicate that chronically applied compressive forces, in the absence of any disease process, caused changes in mechanical properties and composition of tail discs. These changes have similarities and differences in comparison with human spinal disc degeneration.

Mechanical conditions that accelerate intervertebral disc degeneration: overload versus immobilization.

Study Design. A review of the literature on macromechanical factors that accelerate disc degeneration with particular focus on distinguishing the roles of immobilization and overloading. Objective. This review examines evidence from the literature in the areas of biomechanics, epidemiology, animal models, and intervertebral disc physiology. The purpose is to examine: 1) what are the degeneration-related alterations in structural, material, and failure properties in the disc; and 2) evidence in the literature for causal relationships between mechanical loading and alterations in those structural and material properties that constitute disc degeneration. Summary of Background Data. It is widely assumed that the mechanical environment of the intervertebral disc at least in part determines its rate of degeneration. However, there are two plausible and contrasting theories as to the mechanical conditions that promote degeneration: 1) mechanical overload; and 2) reduced motion and loading. Results. There are a greater number of studies addressing the “wear and tear” theory than the immobilization theory. Evidence is accumulating to support the notion that there is a “safe window” of tissue mechanical conditions in which the discs remain healthy. Conclusions. It is concluded that probably any abnormal loading conditions (including overload and immobilization) can produce tissue trauma and/or adaptive changes that may result in disc degeneration. Adverse mechanical conditions can be due to external forces, or may result from impaired neuromuscular control of the paraspinal and abdominal muscles. Future studies will need to evaluate additional unquantified interactions between biomechanics and factors such as genetics and behavioral responses to pain and disability.

Degeneration and aging affect the tensile behavior of human lumbar anulus fibrosus.

Studyb Design Samples of human lumbar (L3-L4) anulus fibrosus from four different anatomic sites (anterior outer, posterolateral outer, anterior inner, posterolateral inner), ranging from normal to severely degenerate, were studied in uniaxial tension and measured for water content. Objectives To evaluate the effects of aging and degeneration on the tensile properties and hydration of the anulus fibrosus in a site-specific manner, The relationship between hydration and parameters of the tenaile behavior were investigated. Summary of Background Data Degeneration and aging have been shown to be related to dramatic changes in the composition and structure of the anulus fibrosus. The associated changes in the tensile, compressive, and shear properties of the anulus fibrosus have not been documented. Numerical studies using finite element models have attempted to simulate the degenerative process by incorporating estimated mechanical properties meant to represent the degenerate anulus fibrosus. Their results present findings that suggest that altered material properties of the anulus fibrosus affect the mechanics of the entire intervertebral disc. Methods Samples of human lumbar anulus fibrosus were classified by grade of degeneration based on a morphologic grading scheme. Multiple layer anulus specimens from four sites in the disc were tested in uniaxial tension under quasistatic conditions in a physiologic saline bath. The tensile modulus, prission;s ratio failure stress and strain, the strain energy density to failure, and the corresponding hydration were determined for each test sample. Result The possons ratio, Failure stress, and strain energy density of the anulus fibrosus were found to be affected significantly by degeneration, with some evldence of a sensitivity of the tensile modulus to gradeof degeneration. All nmaterial properties were found to exhibit a significant and greater dependence on site within the disc than on degenerative grade. Weak corelations between aging and the Poissons ratio and strain energy density were observed. Water content of anulus fibrosus tissue was not affected by degeneration or again, although correlations with tensile properties fwere observed. Conclusions The dramatic changes in morphology, composition, and structure that occur in anulus fibrosus with agin and degeneration are accompanied by specific variations in the tensile properties, Which were generally small in magnitude. Position of the anulus fibrosus within the intertebral disc, particularly in the radial direction, appeared to be the most important variable affecting anulus fibrosus tensile properties. This dependence on position did not change with either aging or degeneration. Results from the present study may be useful in future finite element models to assess how altered material properties of the anulus fibrosus during degeneration and aging may affect the mechanics of the entire intervertebral disc.

Tensile properties of nondegenerate human lumbar anulus fibrosus

Study Design The in vitro tensile behavior of multiple‐layer samples of anulus fibrosus were investigated from nondegenerate intervertebral discs. Objectives To quantify the intrinsic tensile behavior of nondegenerate anulus fibrosus and the variations with position and age in the intervertebral disc. Summary of Background Data Tension is an important loading mode in the anulus fibrosus. The tensile behavior of single‐ and multiple‐layer samples of anulus fibrosus has been shown to vary with specimen orientation, position in the disc, and environmental conditions. Little is known of the changes in these site‐specific tensile properties of the anulus with aging or degeneration of the intervertebral disc. Methods Multiple‐layer specimens of anulus fibrosus were harvested with an orientation parallel to the circumference of the disc. Constant strain rate and uniaxial tensile tests were performed in 0.15 mol/l NaCl at slow strain rates to measure the intrinsic properties of the collagen‐proteoglycan matrix of the anulus fibrosus. The tensile modulus, failure stress, failure strain, and strain energy density were determined. Statistical analyses were done to evaluate regional and age‐related differences in these properties. Results Significant radial and circumferential variations in the intrinsic tensile properties of anular samples were detected. The anterior anulus fibrosus had larger values for tensile moduli and failure stresses than the posterolateral anulus. Also, the outer regions of the anulus had greater moduli and failure stresses and lower failure strains than the inner regions. Strain energy density did not vary significantly with region. Significant, but very weak, correlations were detected between tensile properties and age of the intervertebral disc. Conclusions The observed variations in tensile behavior of multiple‐layer anulus samples indicate that larger variations in tensile modulus and failure properties occur with radial position in the disc than from anterior to posterolateral regions. This pattern is likely related to site‐specific variations in the tensile properties of the single‐layer samples of anulus fibrosus lamellae and the organization of successive lamellae and their interactions. The results of the present study suggest that factors other than age, such as compositional and structural variations in the disc, are the most important determinants of tensile behavior of the anulus fibrosus.

Effects of immobilization and dynamic compression on intervertebral disc cell gene expression in vivo

Study Design. An in vivo analysis of the intervertebral disc’s cellular response to dynamic compression and immobilization was performed using a rat-tail model. Objective. To assess the effects of immobilization and short-term dynamic compression on intervertebral disc cell expression of anabolic and catabolic genes. Summary of Background Data. Static compressive loads applied in vivo alter the composition of the disc matrix and cell viability in a dose-dependent manner. The effects of in vivo dynamic compression, which is a more physiologic load, and reported risk factor for low back pain have not been investigated. Methods. An Ilizarov-type device was implanted on the rat tail and used to determine the effects from 72 hours of immobilization (n = 6), 2 hours of dynamic compression (1 MPa/0.2 Hz) (n = 8), and the coupled effect of immobilization followed by compression (n = 8). Real-time reverse transcription-polymerase chain reaction was used to measure changes in anabolic and catabolic gene levels relative to both internal control subjects and a sham-operated group (n = 7). Results. Immobilization and dynamic compression affect anabolic and catabolic genes, with an overall downregulation of types 1 and 2 collagen and upregulation of aggrecanase, collagenase, and stromelysin in the anulus. The effects of immobilization and compression appear to be additive for collagen types 1 and 2 in the anulus, but not in the nucleus, and not for catabolic genes. Conclusions. Short-duration dynamic compression and immobilization alter gene expression in the rat disc. In studying the response of the disc to loading, it is necessary to look at both anabolic and catabolic pathways, and to consider strain history.

Role of biomechanics in intervertebral disc degeneration and regenerative therapies: what needs repairing in the disc and what are promising biomaterials for its repair?

BACKGROUND CONTEXT Degeneration and injuries of the intervertebral disc (IVD) result in large alterations in biomechanical behaviors. Repair strategies using biomaterials can be optimized based on the biomechanical and biological requirements of the IVD. PURPOSE To review the present literature on the effects of degeneration, simulated degeneration, and injury on biomechanics of the IVD, with special attention paid to needle puncture injuries, which are a pathway for diagnostics and regenerative therapies and the promising biomaterials for disc repair with a focus on how those biomaterials may promote biomechanical repair. STUDY DESIGN A narrative review to evaluate the role of biomechanics on disc degeneration and regenerative therapies with a focus on what biomechanical properties need to be repaired and how to evaluate and accomplish such repairs using biomaterials. Model systems for the screening of such repair strategies are also briefly described. METHODS Articles were selected from two main PubMed searches using keywords: intervertebral AND biomechanics (1,823 articles) and intervertebral AND biomaterials (361 articles). Additional keywords (injury, needle puncture, nucleus pressurization, biomaterials, hydrogel, sealant, tissue engineering) were used to narrow the articles down to the topics most relevant to this review. RESULTS Degeneration and acute disc injuries have the capacity to influence nucleus pulposus (NP) pressurization and annulus fibrosus (AF) integrity, which are necessary for an effective disc function and, therefore, require repair. Needle injection injuries are of particular clinical relevance with the potential to influence disc biomechanics, cellularity, and metabolism, yet these effects are localized or small and more research is required to evaluate and reduce the potential clinical morbidity using such techniques. NP replacement strategies, such as hydrogels, are required to restore the NP pressurization or the lost volume. AF repair strategies including cross-linked hydrogels, fibrous composites, and sealants offer promise for regenerative therapies to restore AF integrity. Tissue engineered IVD structures, as a single implantable construct, may promote greater tissue integration due to the improved repair capacity of the vertebral bone. CONCLUSIONS IVD height, neutral zone characteristics, and torsional biomechanics are sensitive to specific alterations in the NP pressurization and AF integrity and must be addressed for an effective functional repair. Synthetic and natural biomaterials offer promise for NP replacement, AF repair, as an AF sealant, or whole disc replacement. Meeting mechanical and biological compatibilities are necessary for the efficacy and longevity of the repair.

In Vivo Remodeling of Intervertebral Discs in Response to Short- and Long-Term Dynamic Compression

This study evaluated how dynamic compression induced changes in gene expression, tissue composition, and structural properties of the intervertebral disc using a rat tail model. We hypothesized that daily exposure to dynamic compression for short durations would result in anabolic remodeling with increased matrix protein expression and proteoglycan content, and that increased daily load exposure time and experiment duration would retain these changes but also accumulate changes representative of mild degeneration. Sprague‐Dawley rats (n = 100) were instrumented with an Ilizarov‐type device and divided into three dynamic compression (2 week–1.5 h/day, 2 week–8 h/day, 8 week–8 h/day at 1 MPa and 1 Hz) and two sham (2 week, 8 week) groups. Dynamic compression resulted in anabolic remodeling with increased matrix mRNA expression, minimal changes in catabolic genes or disc structure and stiffness, and increased glysosaminoglycans (GAG) content in the nucleus pulposus. Some accumulation of mild degeneration with 8 week–8 h included loss of annulus fibrosus GAG and disc height although 8‐week shams also had loss of disc height, water content, and minor structural alterations. We conclude that dynamic compression is consistent with a notion of “healthy” loading that is able to maintain or promote matrix biosynthesis without substantially disrupting disc structural integrity. A slow accumulation of changes similar to human disc degeneration occurred when dynamic compression was applied for excessive durations, but this degenerative shift was mild when compared to static compression, bending, or other interventions that create greater structural disruption.

Effects of Mechanical Loading on Intervertebral Disc Metabolism In Vivo

The overall goal of this work is to define more clearly which mechanical loading conditions are associated with accelerated disc degeneration. This article briefly reviews recent studies describing the effects of mechanical loading on the metabolism of intervertebral disc cells and defines hypothetical models that provide a framework for quantitative relationships between mechanical loading and disc-cell metabolism. Disc cells respond to mechanical loading in a manner that depends on loading magnitude, frequency, and duration. On the basis of the current data, four models have been proposed to describe the effects of continuous loading on cellular metabolism: (1) on/off response, in which messenger ribonucleic acid (mRNA) transcription remains altered for the duration of loading; (2) maintenance, characterized by an initial change in mRNA levels with return to baseline levels; (3) adaptation, in which mRNA transcription is altered and remains at a new steady state; and (4) no response. In addition, five hypothetical mechanisms that describe the long-term consequences of these metabolic changes on disc-remodeling are presented. The transient nature of gene expression along with enzyme activation/inhibition is associated with changes at the protein level. The hypothetical models presented provide a framework for obtaining quantitative relationships between mechanical loading, gene expression, and changes at the compositional level; however, additional factors, such as regulatory mechanisms, must also be considered when describing disc-remodeling. A more quantitative relationship between mechanical loading effects and the metabolic response of the disc will contribute to injury prevention, facilitate more effective rehabilitation treatments, and help realize the potential of biologic and tissue engineering approaches toward disc repair.

Needle puncture injury affects intervertebral disc mechanics and biology in an organ culture model

Study Design. A bovine intervertebral disc organ culture model was used to study the effect of needle puncture injury on short-term disc mechanics and biology. Objective. To test the hypothesis that significant changes in intervertebral disc structure, mechanics, and cellular response would be present within 1 week of needle puncture injury with a large-gauge needle but not with a small-gauge needle. Summary of Background Data. Defects in anulus fibrosus induced by needle puncture injury can compromise mechanical integrity of the disc and lead to degeneration in animal models. The immediate and short-term mechanical and biologic response to anulus injury through needle puncture in a large animal model is not known. Methods. Bovine caudal intervertebral discs were harvested, punctured posterolaterally using 25G and 14G needles, and placed in organ culture for 6 days. Discs underwent a daily dynamic compression loading protocol for 5 days from 0.2 to 1 MPa at 1 Hz for 1 hour. Disc structure and function were assessed with measurements of dynamic modulus, creep, height loss, water content, proteoglycan loss to the culture medium, cell viability, and histology. Results. Needle puncture injury caused a rapid decrease in dynamic modulus and increase in creep during 1-hour loading, although no changes were detected in water content, disc height, or proteoglycan lost to the media. Cell viability was maintained except for localized cell death at the needle insertion site. An increase in cell number and possible remodeling response was seen in the insertion site in the nucleus pulposus. Conclusion. Relatively minor disruption in the disc from needle puncture injury had immediate and progressive mechanical and biologic consequences with important implications for the use of discography, and repair-regeneration techniques. Results also suggest diagnostic techniques sensitive to mechanical changes in the disc may be important for early detection of degenerative changes in response to anulus injury.