Deva D. Chan

In situ deformation of cartilage in cyclically loaded tibiofemoral joints by displacement-encoded MRI

OBJECTIVES Cartilage displacement and strain patterns were documented noninvasively in intact tibiofemoral joints in situ by magnetic resonance imaging (MRI). This study determined the number of compressive loading cycles required to precondition intact joints prior to imaging, the spatial distribution of displacements and strains in cartilage using displacement-encoded MRI, and the depth-dependency of these measures across specimens. DESIGN Juvenile porcine tibiofemoral joints were cyclically compressed at one and two times body weight at 0.1 Hz to achieve a quasi-steady state load-displacement response. A 7.0 T MRI scanner was used for displacement-encoded imaging with stimulated echoes and a fast spin echo acquisition (DENSE-FSE) in eight intact joints. Two-dimensional displacements and strains were determined throughout the thickness of the tibial and femoral cartilage and then normalized over the tissue thickness. RESULTS Two-dimensional displacements and strains were heterogeneous through the depth of femoral and tibial cartilage under cyclic compression. Strains in the loading direction were compressive and were maximal in the middle zone of femoral and tibial cartilage, and tensile strains were observed in the direction transverse to loading. CONCLUSIONS This study determined the depth-dependent displacements and strains in intact juvenile porcine tibiofemoral joints using displacement-encoded imaging. Displacement and strain distributions reflect the heterogeneous biochemistry of cartilage and the biomechanical response of the tissue to compression in the loading environment of an intact joint. This unique information about the biomechanics of cartilage has potential for comparisons of healthy and degenerated tissue and in the design of engineered replacement tissues.

Articular Cartilage Deformation Determined in an Intact Tibiofemoral Joint by Displacement-Encoded Imaging

This study demonstrates the in vitro displacement and strain of articular cartilage in a cyclically‐compressed and intact joint using displacement‐encoded imaging with stimulated echoes (DENSE) and fast spin echo (FSE). Deformation and strain fields exhibited complex and heterogeneous patterns. The displacements in the loading direction ranged from −1688 to −1481 μm in the tibial cartilage and from −1601 to −764 μm in the femoral cartilage. Corresponding strains ranged from −9.8% to 0.7% and from −4.3% to 0.0%. The displacement and strain precision were determined to be 65 μm and less than 0.2%, respectively. Displacement‐encoded magnetic resonance imaging is capable of determining the nonuniform displacements and strains in the articular cartilage of an intact joint to a high precision. Knowledge of these nonuniform strains is critical for the in situ characterization of normal and diseased tissue, as well as the comprehensive evaluation of repair constructs designed using regenerative medicine. Magn Reson Med, 2009.

In vivo articular cartilage deformation: noninvasive quantification of intratissue strain during joint contact in the human knee

The in vivo measurement of articular cartilage deformation is essential to understand how mechanical forces distribute throughout the healthy tissue and change over time in the pathologic joint. Displacements or strain may serve as a functional imaging biomarker for healthy, diseased, and repaired tissues, but unfortunately intratissue cartilage deformation in vivo is largely unknown. Here, we directly quantified for the first time deformation patterns through the thickness of tibiofemoral articular cartilage in healthy human volunteers. Magnetic resonance imaging acquisitions were synchronized with physiologically relevant compressive loading and used to visualize and measure regional displacement and strain of tibiofemoral articular cartilage in a sagittal plane. We found that compression (of 1/2 body weight) applied at the foot produced a sliding, rigid-body displacement at the tibiofemoral cartilage interface, that loading generated subject- and gender-specific and regionally complex patterns of intratissue strains, and that dominant cartilage strains (approaching 12%) were in shear. Maximum principle and shear strain measures in the tibia were correlated with body mass index. Our MRI-based approach may accelerate the development of regenerative therapies for diseased or damaged cartilage, which is currently limited by the lack of reliable in vivo methods for noninvasive assessment of functional changes following treatment.

Transient and Microscale Deformations and Strains Measured under Exogenous Loading by Noninvasive Magnetic Resonance

Characterization of spatiotemporal deformation dynamics and material properties requires non-destructive methods to visualize mechanics of materials and biological tissues. Displacement-encoded magnetic resonance imaging (MRI) has emerged as a noninvasive and non-destructive technique used to quantify deformation and strains. However, the techniques are not yet applicable to a broad range of materials and load-bearing tissues. In this paper, we visualize transient and internal material deformation through the novel synchrony of external mechanical loading with rapid displacement-encoded MRI. We achieved deformation measurements in silicone gel materials with a spatial resolution of 100 µm and a temporal resolution (of 2.25 ms), set by the repetition time (TR) of the rapid MRI acquisition. Displacement and strain precisions after smoothing were 11 µm and 0.1%, respectively, approaching cellular length scales. Short (1/2 TR) echo times enabled visualization of in situ deformation in a human tibiofemoral joint, inclusive of multiple variable T2 biomaterials. Moreover, the MRI acquisitions achieved a fivefold improvement in imaging time over previous technology, setting the stage for mechanical imaging in vivo. Our results provide a general approach for noninvasive and non-destructive measurement, at high spatial and temporal resolution, of the dynamic mechanical response of a broad range of load-bearing materials and biological tissues.

Stress distributions and material properties determined in articular cartilage from MRI-based finite strains

The noninvasive measurement of finite strains in biomaterials and tissues by magnetic resonance imaging (MRI) enables mathematical estimates of stress distributions and material properties. Such methods allow for non-contact and patient-specific modeling in a manner not possible with traditional mechanical testing or finite element techniques. Here, we employed three constitutive (i.e. linear Hookean, and nonlinear Neo-Hookean and Mooney-Rivlin) relations with known loading conditions and MRI-based finite strains to estimate stress patterns and material properties in the articular cartilage of tibiofemoral joints. Displacement-encoded MRI was used to determine two-dimensional finite strains in juvenile porcine joints, and an iterative technique estimated stress distributions and material properties with defined constitutive relations. Stress distributions were consistent across all relations, although the stress magnitudes varied. Material properties for femoral and tibial cartilage were found to be consistent with those reported in literature. Further, the stress estimates from Hookean and Neo-Hookean, but not Mooney-Rivlin, relations agreed with finite element-based simulations. A nonlinear Neo-Hookean relation provided the most appropriate model for the characterization of complex and spatially dependent stresses using two-dimensional MRI-based finite strain. These results demonstrate the feasibility of a new and computationally efficient technique incorporating MRI-based deformation with mathematical modeling to non-invasively evaluate the mechanical behavior of biological tissues and materials.

Mechanical Deformation and Glycosaminoglycan Content Changes in a Rabbit Annular Puncture Disc Degeneration Model

Study Design. Evaluation of degenerated intervertebral discs from a rabbit annular puncture model by using specialized magnetic resonance imaging (MRI) techniques, including displacement encoding with stimulated echoes and a fast-spin echo (DENSE-FSE) acquisition and delayed gadolinium-enhanced MRI of cartilage (dGEMRIC). Objective. To evaluate a rabbit disc degeneration model by using various MRI techniques. To determine the displacements and strains, spin-lattice relaxation time (T1), and glycosaminoglycan (GAG) distribution of degenerated discs as compared to normal and adjacent level discs. Summary of Background Data. Annular puncture of the intervertebral disc produces disc degeneration in rabbits. DENSE-FSE has been previously demonstrated in articular cartilage for the measurement of soft tissue displacements and strains. MRI also can measure the T1 of tissue, and dGEMRIC can quantify GAG concentration in cartilage. Methods. In eight New Zealand white rabbits, the annulus fibrosis of a lumbar disc was punctured. After 4 weeks, the punctured and cranially adjacent motion segments were isolated for MRI and histology. MRI was used to estimate the disc volume and map T1. DENSE-FSE was used to determine displacements for the estimation of strains. dGEMRIC was then used to determine GAG distributions. Results. Histology and standard MRI indicated degeneration in punctured discs. Disc volume increased significantly at 4 weeks after the puncture. Displacement of the nucleus pulposus was distinct from that of the annulus fibrosis in most untreated discs but not in punctured discs. T1 was significantly higher and GAG concentration significantly lower in punctured discs compared with untreated adjacent level discs. Conclusion. Noninvasive and quantitative MRI techniques can be used to evaluate the mechanical and biochemical changes that occur with animal models of disc degeneration. DENSE-FSE, dGEMRIC, and similar techniques have potential for evaluating the progression of disc degeneration and the efficacy of treatments.

Probing articular cartilage damage and disease by quantitative magnetic resonance imaging

Osteoarthritis (OA) is a debilitating disease that reflects a complex interplay of biochemical, biomechanical, metabolic and genetic factors, which are often triggered by injury, and mediated by inflammation, catabolic cytokines and enzymes. An unmet clinical need is the lack of reliable methods that are able to probe the pathogenesis of early OA when disease-rectifying therapies may be most effective. Non-invasive quantitative magnetic resonance imaging (qMRI) techniques have shown potential for characterizing the structural, biochemical and mechanical changes that occur with cartilage degeneration. In this paper, we review the background in articular cartilage and OA as it pertains to conventional MRI and qMRI techniques. We then discuss how conventional MRI and qMRI techniques are used in clinical and research environments to evaluate biochemical and mechanical changes associated with degeneration. Some qMRI techniques allow for the use of relaxometry values as indirect biomarkers for cartilage components. Direct characterization of mechanical behaviour of cartilage is possible via other specialized qMRI techniques. The combination of these qMRI techniques has the potential to fully characterize the biochemical and biomechanical states that represent the initial changes associated with cartilage degeneration. Additionally, knowledge of in vivo cartilage biochemistry and mechanical behaviour in healthy subjects and across a spectrum of osteoarthritic patients could lead to improvements in the detection, management and treatment of OA.

Mechanostasis in apoptosis and medicine

Mechanostasis describes a complex and dynamic process where cells maintain equilibrium in response to mechanical forces. Normal physiological loading modes and magnitudes contribute to cell proliferation, tissue growth, differentiation and development. However, cell responses to abnormal forces include compensatory apoptotic mechanisms that may contribute to the development of tissue disease and pathological conditions. Mechanotransduction mechanisms tightly regulate the cell response through discrete signaling pathways. Here, we provide an overview of links between pro- and anti-apoptotic signaling and mechanotransduction signaling pathways, and identify potential clinical applications for treatments of disease by exploiting mechanically-linked apoptotic pathways.

Intervertebral disc internal deformation measured by displacements under applied loading with MRI at 3T

Noninvasive assessment of tissue mechanical behavior could enable insights into tissue function in healthy and diseased conditions and permit the development of effective tissue repair treatments. Measurement of displacements under applied loading with MRI (dualMRI) has the potential for such biomechanical characterization on a clinical MRI system.

Deficiency of hyaluronan synthase 1 (Has1) results in chronic joint inflammation and widespread intra-articular fibrosis in a murine model of knee joint cartilage damage

OBJECTIVE Articular cartilage defects commonly result from traumatic injury and predispose to degenerative joint diseases. To test the hypothesis that aberrant healing responses and chronic inflammation lead to osteoarthritis (OA), we examined spatiotemporal changes in joint tissues after cartilage injury in murine knees. Since intra-articular injection of hyaluronan (HA) can attenuate injury-induced osteoarthritis in wild-type (WT) mice, we investigated a role for HA in the response to cartilage injury in mice lacking HA synthase 1 (Has1(-/-)). DESIGN Femoral groove cartilage of WT and Has1(-/-) mice was debrided to generate a non-bleeding wound. Macroscopic imaging, histology, and gene expression were used to evaluate naïve, sham-operated, and injured joints. RESULTS Acute responses (1-2 weeks) in injured joints from WT mice included synovial hyperplasia with HA deposition and joint-wide increases in expression of genes associated with inflammation, fibrosis, and extracellular matrix (ECM) production. By 4 weeks, some resurfacing of damaged cartilage occurred, and early cell responses were normalized. Cartilage damage in Has1(-/-) mice also induced early responses; however, at 4 weeks, inflammation and fibrosis genes remained elevated with widespread cartilage degeneration and fibrotic scarring in the synovium and joint capsule. CONCLUSIONS We conclude that the ineffective repair of injured cartilage in Has1(-/-) joints can be at least partly explained by the markedly enhanced expression of particular genes in pathways linked to ECM turnover, IL-17/IL-6 cytokine signaling, and apoptosis. Notably, Has1 ablation does not alter gross HA content in the ECM, suggesting that HAS1 has a unique function in the metabolism of inflammatory HA matrices.