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. Author manuscript; available in PMC: 2014 Jul 10.
Published in final edited form as: J Orthop Res. 2011 Mar 28;29(9):1312–1319. doi: 10.1002/jor.21381

Local Tissue Properties of Human Osteoarthritic Cartilage Correlate with Magnetic Resonance T1rho Relaxation Times

SY Tang 1,+, RB Souza 2,+, M Ries 1, PK Hansma 3, T Alliston 1,*, X Li 2,*
PMCID: PMC4092115  NIHMSID: NIHMS598085  PMID: 21445940

Abstract

Objective

The objective of this study is to examine the local relationship between T1ρ relaxation times and the mechanical behavior of human osteoarthritic articular cartilage using high-resolution magnetic resonance imaging (MRI) and local in situ microindentation.

Methods

Seven human tibial plateaus were obtained from patients who underwent total knee arthroplasty due to severe OA. Three to six sites were selected from each sample for visual classification using the ICRS Outerbridge scale (total thirty-six sites). Samples were imaged by MR, and the local distribution of T1ρ relaxation times were obtained at these selected sites. The elastic and the viscoelastic characteristics of the tissue were quantified non-destructively using dynamic microindentation to measure peak dynamic modulus, energy dissipation, and phase angle.

Results

Measured Outerbridge scores, MR T1ρ relaxation times and mechanical properties were highly heterogeneous across each cartilage surface. Site-specific measures of T1ρ relaxation times correlated significantly with the phase angle (p < 0.001; R = 0.908), a viscoelastic mechanical behavior of the cartilage.

Conclusions

The novel combination of high resolution MR imaging and microindentation allows the investigation of the local relationship between quantitative MRI and biomechanical properties in highly heterogeneous OA cartilage. These findings suggest that MRI T1ρ can provide a functional assessment of articular cartilage.

Keywords: cartilage, osteoarthritis, magnetic resonance imaging, tissue viscoelasticity, T1rho

Introduction

OA is associated with biochemical and physical changes in the extracellular matrix of the articular cartilage that ultimately lead to pain and loss of mechanical function of the diarthroidal joint1. Although the exact etiology of OA remains unclear, many of these changes occur gradually at the matrix level prior to clinical manifestation. Thus the ability to detect these changes at an early stage may provide diagnostic and therapeutic insights towards OA.

The mechanical behavior of articular cartilage is derived from the triphasic interactions between its primary constituents of collagen, proteoglycans, and water2. For example, the collagen network in cartilage is optimized to resist shear and tensile strains, and it also provides attachment for the negatively charged proteoglycan network3 that can resist compressive loading2. Proteoglycans nucleate cationic fluids to provide additional deformation resistance. The interactions between these phases provide time-dependent and nonlinear deformation responses to mechanical load4. Trauma and pathologies such as OA induce changes including proteoglycan loss, increased water content at early stages then dehydration at late stages, and disorganization of the collagen network5, culminating in cartilage degeneration. These changes in matrix composition are known to correspond to alterations in the matrix mechanical behavior6.

Magnetic resonance imaging (MRI) of articular cartilage is a useful clinical tool to provide quantitative analyses of cartilage morphology. Recent advances in quantitative MR analysis, including T1ρ7–9 and T210–12 relaxation time quantification as well as delayed Gadolinium Enhanced MRI of Cartilage (dGEMRIC) 13,14, have shown promising relationships between tissue relaxation times and cartilage biochemistry and composition. These techniques facilitate non-invasive quantitative assessment of cartilage composition and has great potential for detecting early degeneration in cartilage 15–18.

Previous studies further investigated the relationship between MR imaging parameters and tissue mechanical behavior. Using dGEMRIC, some studies have reported strong relationships (R = 0.90) with cartilage stiffness measures,12,19–22, and others have reported relationships between cartilage T2 times and various mechanical properties 12,21,22. One previous study reported association between T1ρ relaxation times and tissue mechanical properties in bovine cartilage 9, however, currently no studies have investigated this relationship in naturally degenerated human osteoarthritic cartilage. Furthermore, previous studies used primarily confined compression methods for mechanical testing, which provides the biomechanical properties of the whole punch taken. In this study, using a combination of high-resolution magnetic resonance imaging and local in situ microindentation, we investigate the relationship between the local mechanical behavior of human osteoarthritic articular cartilage and MR T1ρ relaxation times. We hypothesize that quantitative MRI may be able to detect local changes in cartilage mechanical behavior.

Methods

Specimen preparation

Seven human tibial plateaus were obtained from patients who underwent total knee arthroplasty (TKA) due to severe OA in accordance with protocols approved by the Committee on Human Research at the University of California, San Francisco. Specimens were frozen immediately post-surgery and stored at −80°C. Prior to the MR analysis, specimens were thawed overnight at 4°C. The knee cartilage specimens were mounted on a radiographically opaque plastic grid for location reference. Simethicone was applied to both the cartilage surface and the distal bone surface to minimize biochemical exchanges between specimens and solution, and to reduce accumulation of air bubbles on tissue surfaces. After preparation, the specimens were stored at room temperature, immersed in phosphate-buffered saline (PBS), for approximately thirty minutes before the MR scan.

Grading of cartilage degeneration

The indentation sites and the immediate surrounding cartilage regions were visually inspected by an experienced orthopaedic surgeon (M.R.) and rated in accordance to the International Cartilage Repair Society (ICRS) Outerbridge scores ranging from 1 – 423.

T1ρ Magnetic Resonance Imaging Acquisition

The samples were scanned on a GE 3T Signa EXCITE MRI scanner (General Electric, Milwaukee, WI) using an 8-channel phased-array knee coil (Invivo, Orlando, FL). All samples were evaluated on sagittal 3D T1ρ-weighted images based on spoiled gradient echo (SPGR) acquisition using a previously developed sequence 24 with these parameters: TR/TE = 9.3/3.7 ms; FOV = 6–8 cm, matrix = 256 × 128, slice thickness = 2 mm, BW = 31.25 kHz, VPS = 64, Trec = 1.5 s, TSL = 0, 10, 40, 80 ms, FSL = 500 Hz. In plane resolution for the map sequence was 0.3 × 0.3 mm. T1ρ maps were quantified by fitting the image intensity of T1ρ-weighted images pixel-by-pixel to the equation S(TSL) ∝ S0*exp(−TSL/T1ρ) using a Levenberg-Marquardt mono-exponential fitting algorithm.

Mechanical testing by microindentation

Indentations to determine the cartilage matrix mechanical behavior were performed immediately following MR imaging. Between three and six sites were selected per tibial plateau based on the grid system dependent upon the presence of existing cartilage for a total of thirty-six indentation sites that corresponded with reconstructed regions of interest of the MR scans. Each site was at least 12.7 mm apart to allow greater sampling of tissue variability. Dynamic indentations were done in situ with the sample submerged in PBS at 20° C using an indenter (BioDent 1000 TDI, Active Life Tech, CA)25 (Figure 1A, 1B). The indenter was fixed in place using a rigid mount that allowed precise axial movements that lowered the indenter onto the test sites. Using a reference probe to identify the articular surface, a 1.47 mm diameter cylindrical probe cyclically indented the tissue to a depth of 150 μm at 2 Hz. At each site, the dynamic microindentations were allowed to cycle for 90 seconds with the above parameters, and five sets of force-displacement curves of 2-second long time periods were obtained at evenly spaced time intervals over the 90 seconds. Preliminary studies following this protocol on cartilage showed that repeated measurements on the same site resulted in variability on the order of 3 – 5% between measurements. Great care was taken in ensuring planar correspondence between MRI voxel evaluation and mechanical indentation. Force-displacement data was collected and used to compute mechanical parameters including peak indentation force (Fmax); peak dynamic modulus (PDM), which was computed from the slope determined from linear regression of the maximum 20% of the loading curve26; energy dissipation (ED), which was determined by the area enclosed by the force-displacement curve; and phase angle, determined by the tangent of the phase lag “δ” between force and displacement peaks (Figure 1C, 1D).

Figure 1.

Figure 1

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Schematic of the microindentation tests on the articular cartilage of the tibial plateau. [A] The microindentation is performed with a reference probe resting on the surface of the cartilage, while the indentation probe travels axially within the reference probe. The probe in this panel is in the retracted position. [B] The indentation probe extends into the tissue down to a depth of 150 μm. [C] The force-displacement data is collected, and the peak force, peak dynamic modulus, and energy dissipation is computed from this data. [D] The phase lag δ, from which the quantity phase angle (tangent δ) is computed, is measured from the time shift between the minimum force and displacements.

Histology

Following MRI and microindentation, representative specimens were fixed in 10% formalin and embedded in paraffin. Sections were generated (10 μm thickness) in the same plane as the ex vivo MRI and stained with hematoxylin and eosin (H&E) to evaluate tissue micro-morphology and the extent of degeneration.

Quantification of T1ρ relaxation times

Regions of interest (ROI) corresponding to each indentation site were carefully identified using the plastic grid landmarks on T1ρ-weighted images with TSL = 0 ms. Each ROI was 6 pixels wide and 2 pixels deep, based on the size and depth of the indentations. The depth of ROIs from the cartilage joint interface was determined based on the maximum principal stresses due to indentation calculated from the finite element analysis as detailed below. The mean T1ρ relaxation time values were computed from the defined ROIs (Figure 2B).

Figure 2.

Figure 2

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Registration of in situ dynamic indentation testing with MRI analysis. [A] A radiographically opaque plastic grid, which the tibial plateau samples were mounted on, provided the landmarks for indentation and MR imaging evaluation. [B] A magnified section is shown from panel A. The T1ρ relaxation times were computed for each site of indentation by averaging the 2nd and 3rd pixels from the cartilage surface as shown by the white enclosed box. This depth corresponds to a depth of 0.6 mm–0.9 mm into the cartilage tissue based on the 0.3 mm MRI T1ρ voxel resolution. The top pixel is excluded from the analyses due to the uncertainty in partial volume effects at the cartilage/synovial fluid interface. [C] A simple finite element contact analysis confirms that the maximum principal stresses due to indentation occur at a depth of 0.9 mm.

Finite element analysis

A two dimensional frictionless contact finite element model was used to determine the depth and distribution of the stress fields across the depth of the cartilage due to the 150 μm surface deformation. The cartilage was modeled as a linearly elastic isotropic material with an elastic modulus (E) of 0.5 MPa and Poisson’s ratio (ν) of 0.5, and the mesh consisted of square elements with 200 μm sides. The 150 μm surface deformation was applied perpendicularly across the top 7 elements consistent with the 1.4 mm diameter of the indentation platen. The stress propagation profile of the finite element analyses suggests that the maximum principal stresses occur within the 0.3 – 0.9 mm depth from the cartilage surface (Figure 2C). A java-based explicit solver was used to conduct these simulations (Impact FEA, Open Source).

Statistical analyses

Correlations accounting for repeated measures27,28 were used to determine the relationships between MR measures (T1ρ relaxation times) and articular cartilage mechanical behavior (Fmax, ED, PDM, and phase angle). All statistical analyses were conducted using Minitab (Minitab USA, PA).

Results

The mean Outerbridge score was 3.2 (standard deviation: 1.4), ranging from 2 to 4. Tissues from the same donor demonstrated variations in the degree of degeneration with scores ranging from 2–4 (Figure 3A–D). Moreover, tissues that were rated the same Outerbridge score displayed a wide range of mechanical properties (Figure 3). The Outerbridge grade did not significantly correlate with the mean T1ρ relaxation times in each graded region (Figure 4). Histology revealed significant degeneration in the studied samples as observed by cartilage thinning, reduced safranin-O staining, and fibrillations of the cartilage tissue. Figure 5 presents a histology section with low T1ρ values and less degeneration (55.2 ± 5.64 ms; Figure 5A, 5C, 5E) and a section with high T1ρ values and more advanced degeneration (83.3 ± 28.1 ms; Figure 5B, 5D, 5F).

Figure 3.

Figure 3

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The mechanical behavior of cartilage tissue was highly heterogeneous. Similar to the variations in observed in Outerbridge scores, the cartilage matrix shows substantial variations in its elastic and viscous mechanical behavior across the articular surface even within sites that have been scored at similar levels of degeneration as evidenced by the [A] peak indentation force, [B] energy dissipation, [C] peak dynamic modulus, and [D] phase angle. The box plot ranges from the 25% to 75% quartiles, while the whiskers extend from the 10% to 90% percentiles. Thirty-six sampled sites from seven tibial plateaus are shown here.

Figure 4.

Figure 4

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Heterogeneity in the cartilage composition using MR imaging. [A] The cartilage tissue exhibits heterogeneous T1ρ signals throughout a typical saggital section of the tibial plateau. The Outerbridge scores for the measurement sites do not correlate with the [B] T1ρ relaxation times measured at the same sites.

Figure 5.

Figure 5

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Cartilage degeneration is detectable by T1ρ MR imaging. The extent of cartilage degeneration corresponded with the T1ρ relaxation times as observed by two samples with [A] low T1ρ and [B] high T1ρ signals. The histological evaluation of the parafinized sections stained with H&E from these same samples at the corresponding sites confirms the degree of degeneration at both [C, D] 10X and [E, F] 20X sections.

T1ρ positively and significantly correlates with the viscoelastic behavior of cartilage matrix, as determined by Phase angle (p < 0.001;R = 0.908) (Table I; Figure 6). Phase angle, a function of the cyclical phase lag between the applied deformation and measured force, describes the cartilage matrix’s relative ability to absorb and dissipate mechanical energy. Energy dissipation showed a moderate but non-significant inverse trend with T1ρ relaxation times (p = 0.102; R = −0.324). Peak indentation force (p = 0.457; R = 0.150) and peak dynamic modulus (p = 0.744; R = 0.0657) showed no apparent correlation with T1ρ relaxation times (Table II).

Table I.

Pearson’s correlations coefficients (R) and respective p-values between local cartilage mechanical properties and MRI T1ρ values.

Mechanical Parameters R p-value
Peak indentation force (Fmax) 0.150 0.457
Energy dissipation (ED) −0.324 0.102
Peak dynamic modulus (PDM) 0.0657 0.744
Phase angle (tan δ) 0.908 <0.001
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Figure 6.

Figure 6

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Robust correlation of T1ρ with viscoelastic properties of cartilage matrix. Phase angle correlated significantly with the T1ρ relaxation times at the same cartilage site (p<0.001; Pearson’s correlation). This data suggest that T1ρ MR imaging may be more sensitive to local alterations in the viscous, rather than elastic, components of the cartilage matrix mechanical behavior. Thirty-six sampled sites from seven tibial plateaus are shown here.

Discussion

Osteoarthritic cartilage is highly heterogeneous as confirmed by clinical Outerbridge scores, quantitative magnetic resonance imaging, and in situ dynamic microindentation. Global measurements may be insensitive to this heterogeneity, and quantitative measurements that are averaged across a bulk region may obscure relationships that may be present at a local level. Using a combination of site-specific high-resolution MR imaging and microindentation, we observed a significant association between T1ρ relaxation times and tissue mechanical behavior at the local tissue level. To date, no other studies have evaluated the relationship between phase angle and quantitative imaging variables in arthritic articular cartilage. Our results show that an increase in T1ρ relaxation time is coupled with a decreased ability of the tissue to resist deformation without mechanical damage at the local level, and the matrix mechanical behavior measured at this scale corresponds remarkably well with evaluated T1ρ values. Taken together, these trends strongly suggest a direct association between noninvasive quantitative imaging and local tissue mechanics.

Several methods have been used to measure and describe the nonlinear mechanical behavior of articular cartilage6,29–32. However, determining the relevant mechanical parameters that characterize the in situ articular cartilage mechanical behavior remains challenging. Dynamic microindentation offers several advantages. Compared to conventional methods, this approach tests intact cartilage tissue at the millimeter scale to more fully account for the effects of local tissue heterogeneity. Directed measurements are made non-destructively at specific sites while maintaining the natural boundary conditions of the cartilage33. In addition, the cyclic nature of the indentation tests allows the evaluation of viscoelastic parameters, which may be important when identifying early cartilage degeneration. The indentation protocol used here has been shown to provide excellent surrogate measurements for conventional tension and compression experiments in elastomeric materials34.

Since the viscoelastic behavior of cartilage has been attributed to the triphasic interactions between collagen, water, and proteoglycan29,35,36, an assessment of cartilage mechanical behavior must account for both the elastic and viscous components of the tissue. Previous work has shown a direct relationship between Outerbridge scores and the elastic modulus of the tissue37. We did not observe this trend, perhaps due to the heterogeneous nature of the cartilage tissue and the fact that the three discrete values in the Outerbridge score do not provide sufficient statistical range for regression analyses. Furthermore, indentation dynamic modulus may be relatively insensitive to degradation of the cartilage matrix6.

Previous studies have shown that MR T1ρ relaxation times of articular cartilage correlate with the amount of proteoglycan in the cartilage matrix7, and the loss of proteoglycans alters the time-dependent mechanical behavior of cartilage33,36. Consistent with the observations on bovine cartilage by Wheaton et al9, we observed changes in the viscoelastic behavior of cartilage tissue, and these changes, particularly phase angle, were significantly correlated with T1ρ times. The phase angle reflects the ratio of dissipated mechanical energy to the stored mechanical energy as the tissue undergoes deformation. Increasing values of phase angle have been shown to indicate material degradation in rubbers and rubber-like elastomers38. Increased dissipated mechanical energy may be lost in the form of mechanical damage, such as in the form of fissures and microdamage39,40. Lower values of the phase angle suggest that tissue recovers quickly after unloading; conversely, higher values of the phase angle suggest that the tissue takes longer to recover from the initial deformation. The reduced rate of deformation recovery marked by the increasing phase angle of cartilage characterizes a degenerated state of cartilage with a loss of mechanical function41,42. Since higher values of T1ρ suggest a higher degree of degeneration43, the site-specific correspondence between the increasing phase angle and T1ρ values confirm the adverse changes that are occurring at these sites.

Energy dissipation is another intrinsic property of viscoelastic materials, and represents the repeated formation and breaking of molecular bonds in the material during deformation. Decrease of energy dissipation suggests that the material has a reduced ability to undergo deformation without sustaining irreversible damage. It is thus not surprising that we also observed an inverse trend of energy dissipation and T1ρ relaxation times, albeit non-significant (p = 0.102), suggesting that cartilage degeneration, marked by high T1ρ relaxation times may potentially be coupled with the tissue’s reduced ability to dissipate energy.

It is important to acknowledge the limitations of this study. The heterogeneity of cartilage underscores the importance of careful registration between MRI and mechanical testing. While we used a grid as a registration aid, imaging resolution (2 mm slices) may have limited our ability to precisely match data. The method of selecting data based on two superficial layers of pixels allowed us to directly compare T1ρ values with the mechanical properties that were evaluated at a similar depth. Potential partial volume effects on T1ρ voxel data were minimized by excluding the most superficial pixel layer, where these effects are unavoidable. Nonetheless, some partial volume effects likely remain due to the heterogeneity of the tissue. Lastly, future studies with larger samples are needed to confirm our findings.

In conclusion, the novel combination of high resolution MRI and microindentation allows investigation of local relationships between quantitative MRI and biomechanical properties in highly heterogeneous OA cartilage. Findings from the present study suggest that T1ρ relaxation time mapping is a valuable tool that provides important mechanical information in OA cartilage. In particular, this study identifies that local variation in phase angle – an indicator of the viscoelastic quality of cartilage matrix – is highly correlated to T1ρ relaxation time in articular cartilage. Therefore, T1ρ time mapping is not only useful for detecting early changes in cartilage composition with cartilage degradation, but is also a valuable tool to non-invasively assess the functional changes in the cartilage matrix in the progression of OA.

Acknowledgments

PKH-NIH R01GM65354; TA NIH-R01DE019284; XL-NIH K25AR053633, NIH R21056773. The authors thank Eric Han (GE Healthcare) for help with sequence development.

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