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. Author manuscript; available in PMC: 2017 Nov 13.
Published in final edited form as: MAGMA. 2011 Nov 10;25(4):297–304. doi: 10.1007/s10334-011-0288-1

Orientational Dependent Sensitivities of T2 and T1ρ towards trypsin degradation and Gd-DPTA2− presence in bovine nasal cartilage

Nian Wang 1, Yang Xia 1,*
PMCID: PMC5682561  NIHMSID: NIHMS864006  PMID: 22071581

Abstract

Object

To study the orientational dependencies of T2 and T1ρ in native and trypsin-degraded bovine nasal cartilage, with and without the presence of 1 mM Gd-DTPA2−.

Materials and Methods

Sixteen specimens were prepared in two orthogonal fibril directions (parallel and perpendicular), treated using different protocols (native, Gd treated, and trypsin-treated, combination), and imaged using µMRI at 0° and 55° (the magic angle) fibril orientations with respect to the magnetic field B0. Two-dimensional (2D) T2 and T1ρ images were then calculated quantitatively.

Results

Without Gd, native perpendicular tissues demonstrated significant T1ρ dispersion (including T2 at the zero spin-lock field) at 0° and less dispersion at 55°, while native parallel specimens exhibited smaller T1ρ dispersion at both 0° and 55°. Trypsin degradation caused a minimum 50 % increase in T1ρ. With Gd, trypsin degradation caused significant reduction in T1ρ values up to 60%.

Conclusion

The collagen orientation in nasal cartilage can influence T2 and T1ρ MRI of cartilage. Without Gd, T1ρ was sensitive to the proteoglycan content and its sensitivity was nearly constant regardless of fibril orientation. In comparison, the T2 sensitivity to proteoglycan was dependant upon fibril orientation, i.e., more sensitive at 55° than 0°. When Gd ions were present, both T2 and T1ρ became insensitive to the proteoglycan content.

Keywords: T2, T1ρ, nasal cartilage, collagen fibril, proteoglycan, magic angle, anisotropy, spin lock

Introduction

Articular cartilage is a type of connective tissue covering the end of bones in joints and consists mainly of water, proteoglycans (PG) and collagen fibrils [1–3]. A loss of negatively charged PG macromolecules from the extracellular matrix of cartilage is a hallmark in the early development of osteoarthritis (OA), a disorder affecting a significant portion of the human population. Magnetic resonance imaging (MRI) is the most sensitive medical imaging technique for noninvasive assessment of soft tissue such as cartilage. However, conventional MRI, i.e., intensity based, is insensitive to the subtle biochemical changes associated with the early stage of cartilage lesions [4–6]. Recently, several MRI-based protocols such as gadolinium-enhanced MRI (dGEMRIC) [7–11], sodium MRI [12, 13], anisotropy of T2 relaxation [14–16], and T1ρ relaxation (spin-lattice relaxation in the rotating frame) [17–20], were found to be sensitive to PG content in cartilage.

Transverse relaxation T2 measures the decay in phase coherence between individual nuclear spins and is sensitive to the dipolar interaction due to the anisotropic motion of water molecules, which is primarily modulated by the orientational structure of collagen fibrils in cartilage [14]. Due to the dipolar interaction, shortening T2 values can cause a laminar appearance of articular cartilage in MRI when the local collagen fibrils are orientated parallel with the external magnetic field B0 [14, 21–23]. By rotating the fibril orientation by approximately 55° with respect to B0, the dipolar interaction is minimized thus eliminating the laminar appearance; a result known as the “magic-angle effect” in cartilage MRI literature [15, 16, 24]. As previously stated, a number of studies demonstrate that T2 experiments are sensitive to PG content in tissue [25, 26].

In addition to T2, T1ρ has recently been used in cartilage MRI [17–20, 27–32], since it is sensitive to slow motional interactions between confined water molecules and the macromolecular environment [27, 30]. Recent studies show that the T1ρ relaxation rate (R1ρ = 1/T1ρ) decreases linearly with decreasing PG content and appears more sensitive than T2 toward PG variation in both osteoarthritic human specimens and bovine patellae [29]. It is also reported that the spin-lock technique can eliminate the effect of residual dipolar interaction, which may lead to a more accurate diagnosis of degenerative changes in cartilage [33]. Although T1ρ shows great potential for clinical applications in detecting cartilage degradation, specimen orientation with respect to the main magnetic field B0 has not been extensively discussed.

Another factor related to clinical application of relaxation time is the possible introduction of Gd-DTPA2− ions into cartilage in medical protocols such as dGEMRIC [9]. Several studies in literature discuss T2 dependency on Gd-DTPA2− ions present in tissue [34–36], but rarely T1ρ dependency on Gd-DTPA2− ions. This project has three aims. First, the sensitivities of both T2 and T1ρ relaxation times are studied in native and trypsin-degraded specimens of bovine nasal cartilage (BNC), with and without Gd-DTPA2− ions present. Second, although BNC is commonly used as a model material in the study of connective tissue due to its more homogenous structure, BNC was recently found to possess a certain heterogeneities in fibril organization which can cause measurable anisotropies in polarized light microscopy (PLM), microscopic MRI (µMRI) and mechanical experiments [37, 38]. This µMRI project is carried out with full knowledge of fibril orientation in bovine nasal cartilage specimens. Finally, the effects of specimen orientation in the magnetic field and the dependency of T1ρ on spin-lock field strength are also investigated in this project.

Materials and Methods

Bovine nasal cartilage specimens

Fresh bovine nasal cartilage was obtained from a local slaughter house (C. Roy, Yale, MI). The tissue was immersed in physiological saline (154 mM NaCl in deionized water) with 1 % protease inhibitor (Sigma, Missouri) and stored at −20 °C before experimentation. Sixteen individual specimens, each approximately 1.5×1.5×8 mm3 in size, were harvested from the central part of a large nasal septa in two different orientation groups (Fig 1). Eight specimens were cut such that the collagen fibrils were oriented perpendicular to the tissue block length (perpendicular specimens) and eight were cut such that the collagen fibrils were oriented parallel to the tissue block length (parallel specimens). The collagen fibrils followed a previously determined orientation such that the fibril long axes were oriented parallel to the medial axis of the nasal septum [38].

Figure 1.

Figure 1

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Two different ways of preparing the BNC specimens: (a) perpendicular and (b) parallel. The solid short lines inside the blocks illustrate the orientation of the collagen fibrils in BNC. The specimens were imaged under two orientations with respect to the main magnetic field B0, pointing upwards. The specimen rotation was respect to the long axis of the tissue block.

All specimens were imaged individually using the same MRI protocol prior to any chemical treatment, providing a control MRI. Prior to additional MRI experiments, four specimens from each group were immersed in 1 mM Gd-DTPA2− (gadolinium diethylene triamine pentaacetic acid) solution (Magnevist, Berlex, NJ) in saline with 1 % protease inhibitor (Sigma, Missouri) for approximately 10 hours [10]. The other four specimens from each group were first soaked in 10 µg/ml trypsin solution (Sigma, Missouri) for more than 6 hours to digest proteoglycans [39] then soaked in fresh saline with 1 % protease inhibitor to remove excess trypsin. After repeating MRI, these PG-depleted specimens were immersed in a Gd-DTPA2− solution for more than 10 hours and imaged a third time using the same protocol.

Microscopic MRI (µMRI) Protocols

All µMRI experiments were performed using a Bruker AVANCE II 300 NMR spectrometer equipped with a 7-Tesla/89-mm vertical-bore superconducting magnet and microimaging accessory (Bruker Instrument, Billerica, MA). A homemade 4 mm solenoid coil was used in the µMRI experiments, which produced a 90° hard pulse of 5 µs duration. Quantitative T2-imaging experiments were performed using a CPMG magnetization-prepared T2 imaging sequence [40]. The T1ρ imaging sequence proceeded with a 90° hard pulse followed by a spin-lock pulse. The power of the spin-lock field varied from 0.5 – 6 kHz, i.e, 500, 1000, 2000, 3500, 5000, 6000 Hz, and the spin-lock field strength was calibrated by adjusting the 90° pulse strength.

2D MRI experiments were carried out using an acquisition matrix of 32×32 (100×100 µm pixel resolution) and a slice thickness of 1 mm. The specimen was loaded into the receiver coil and ensured that the long axis of the tissue block was perpendicular to the magnetic field B0 direction, which was used as the reference angle (Fig 1). The specimen blocks were imaged at different orientations with respect to B0, i.e., the 0° and 55° orientations of the perpendicular block were such that the orientations of the collagen fibrils were parallel or at 55° to B0, respectively. The orientations of the parallel blocks were imaged in a similar manner. Since the fibril axis was parallel with the long dimension of the tissue block, the 0°–55° rotation did not change the fibril orientation in the magnetic field for the parallel blocks.

A repetition time (TR) of 2 s was used for specimens without Gd-DTPA2− and 0.8 s for specimens treated with 1mM Gd-DTPA2− since the presence of Gd-DTPA2− shortened the T1 significantly [10]. The echo spacing in the CPMG T2-weighting segment was 1 ms and the number of echoes was 2, 30, 60, 120, 240, which yielded the echo times (TE) of 2, 30, 60, 120, and 240 ms, respectively. The spin-lock pulse durations were 2, 30, 60, 120, and 240 ms for each T1ρ measurement.

2D T1ρ images were calculated pixel-by-pixel using a common equation: Sig(TSL) = Sig0exp(−TSL/ T1ρ) + K, where TSL was the time of spin-lock pulse, Sig was the signal intensity of the observed signal, Sig0 was the thermal equilibrium magnetization, and K was a constant offset. 2D T2 images were calculated pixel-by-pixel using a similar equation: Sig(TE) = Sig0exp(−TE/T2)+K, where TE was the echo time. Both calculations were done off-line using a custom Matlab (MathWorks, Natick, MA) code. Since there was no significant variation within the 2D image slice, an 8×8 pixel region-of-interest was chosen from the center of each image and averaged to yield one relaxation value and standard deviation. The averaged relaxation values and standard deviations calculated from each image were used to generate line plots.

Results

Perpendicular BNC specimens

Fig 2 shows the T2 images, the 2 kHz spin-lock field T1ρ images and the dispersion curves of all T1ρ and T2 imaging data from perpendicular specimens. When the spin-lock field is zero, a T1ρ imaging sequence essentially becomes a T2 imaging sequence. For this reason, the T2 results are grouped together with the T1ρ results and T2 is labeled as T1ρ at zero field in the dispersion curves. Several distinct characteristics can be identified in these complex relaxation results. First, the anisotropic effects of both T2 and T1ρ exist in nearly all cases since the relaxation values are always higher when the specimen is oriented at 55° than when at 0° with respect to B0. The greatest relaxation difference as the function of specimen orientation occurs in samples containing no Gd ions and when the spin-lock field is zero (T2 values in Fig 2a and 2c). For tissue subject to an increasingly larger spin-lock field or tissue treated with Gd, the orientation-dependant relaxation variation decreases. Second, T1ρ relaxation is found to be a function of the spin-lock field: the larger the spin-lock field, the longer the T1ρ relaxation. The largest increase in T1ρ relaxation time occurs at low spin-lock fields (less than 2 kHz). Additionally, T1ρ relaxation values increase only slightly when the spin-lock field is higher than 2 kHz. Third, the largest difference between native and degraded tissue occurs when the tissue contains no Gd ions (comparison between Fig 2a and 2c). With the immersion of tissue in Gd solution, both T2 and T1ρ sensitivity toward tissue degradation reduces markedly (comparison between Fig 2b and 2d).

Figure 2.

Figure 2

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T1ρ dispersion plots of the perpendicular specimens with and without Gd-DTPA2− at 0° (open circles) and the magic angle (solid squares) for (a) native specimens, (b) native specimens with Gd-DTPA2−, (c) trypsin-degraded specimens, (d) trypsin-degraded specimens with Gd-DTPA2-. All images were plotted with the same intensity limits (0 – 400 ms) in the usual gray scale.

Parallel BNC specimens

Fig 3 summarizes the T2 images, the T1ρ images at 2 kHz, and the dispersion curves of all T1ρ and T2 imaging data from the parallel specimens. Comparing with the perpendicular samples, the most significant difference is the lack of anisotropic variation between 0° and 55° for both T2 and T1ρ values, which clearly indicates that the fibril orientation in the parallel specimens are parallel with the rotation axis (Fig 1b). Consequently, a rotation of the parallel specimen does not change its fibril orientation in the magnetic field. Apart from this distinction, other features seen in the perpendicular specimens are also present in the parallel specimens.

Figure 3.

Figure 3

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T1ρ dispersion plots of the parallel specimens with and without Gd-DTPA2− at 0° (open circles) and the magic angle (solid squares) for (a) native specimens, (b) native specimens with Gd-DTPA2−, (c) trypsin-degraded specimens, (d) trypsin-degraded specimens with Gd-DTPA2−. All images were plotted with the same intensity limits (0 – 400 ms) in the usual gray scale.

The differences between perpendicular and parallel BNC

To quantify variations of T2 and T1ρ dispersion for different orientations, different spin-lock fields and when under the influence of Gd ions, the complex data shown in Fig 2 and Fig 3 are summarized together in Fig 4 as the percentage ratios (percentage ratio = 100*(treated/control), where the control is any base value of the tissue before the tissue was treated in any procedure (e.g., soaked in Gd, digested in trypsin, or combination treatment).

Figure 4.

Figure 4

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The percentage ratios of T1ρ dispersion plots of the perpendicular specimens (left) and parallel specimens (right), under different experimental conditions. No change would result in a ratio of 100. Increasing or decreasing with respect to the control would result in above 100 or below 100, respectively.

In comparing degraded and native tissues (Fig 4a and Fig 4b), the trypsin digestion causes T1ρ values to increase by at least 50 % (from the 100 % base value to 150–180 %), regardless of (a) whether it is cut in perpendicular or parallel sections, or (b) tissue orientation, as long as Gd ions are not present in the tissue. The only exception is the T2 data of the perpendicular section at 0°, which shows no sensitivity toward tissue degradation. The weakly spin-locked T1ρ data (e.g., less than 1 kHz) appear to have a similar exception as T2, but on a less scale. Fig 4a and Fig 4b also demonstrate that the immersion of tissue in Gd solution completely eliminates the sensitivity of T2 and T1ρ toward tissue degradation. In fact, the ratios of degraded/native are less than the 100% base value, indicating the T2 and T1ρ relaxation values are reduced when Gd ions are present in trypsin-degraded tissue. These data suggest that both T2 and T1ρ are most sensitive to PG loss in cartilage as long as the tissue is not oriented at 0° and there are no Gd ions present.

The effect of Gd ion presence in cartilage is illustrated clearly in Figs 4c and 4d. With the immersion of tissue in a Gd solution, the T1ρ values are reduced by about 20–25 % in native tissues and about 50–60 % in degraded tissues, regardless of specimen orientation in the magnetic field or whether parallel or perpendicularly cut. The only exceptions are the T2 and weakly spin-locked T1ρ (less than 1 kHz) at the 0° specimen orientation. In these specific cases, the influence of Gd on relaxation values is minimal.

The sensitivity of T2 and T1ρ toward tissue degradation

Since there is little difference after the spin-lock field is increased beyond 2 kHz, three representative relaxation parameters, ΔT2, ΔT1ρ(0.5 kHz), and ΔT1ρ(2 kHz), were closely examined for their sensitivities toward tissue degradation in Fig 5, which revealed three distinct features. First, there is little sensitivity in T2 to tissue treatment for all relaxation parameters when the perpendicular specimens are at 0° (the first group of columns in Fig 5a), which illustrates the strong influence of dipolar interaction on the relaxation mechanism. When the dipolar interaction is strong, the T2 is uninfluenced by either native or degraded tissue. Second, with the presence of Gd ions in the tissue, these parameters show little sensitivity toward both native and degraded tissue (white columns in Fig 5), regardless of the specimen orientation (0°, 55°). Finally, these three parameters have good sensitivities in all other situations, with the greatest sensitivity, i.e., the biggest difference, between two distinct situations: (1) degraded tissue with and without the presence of Gd (gray columns), and (2) native tissue versus degraded tissue (shaded columns).

Figure 5.

Figure 5

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The sensitivity (i.e., difference) of (a) T2, (b) T1ρ 500 Hz, and (c) T1ρ 2 kHz of under different experimental conditions.

Discussion

Although nasal cartilage was commonly considered homogenously structured, it was noticed only recently that BNC also possesses some structural anisotropy in its collagen fibril orientation, which could contribute to a number of anisotropies in tissue histology by polarized light microscopy, µMRI and mechanical measurements [37, 38]. In this project, the BNC specimens were carefully prepared in two different fibril orientations, perpendicular and parallel, based on precise knowledge of fibril orientation [38]. Several critical issues related to the sensitivities of T2 and T1ρ measurements toward cartilage degradation were investigated. These issues included: (1) the characteristics of T1ρ dispersion, i.e., the value of T1ρ as a function of the spin-lock field B1, (2) the specimen orientation in the magnetic field B0 and (3) the PG content in the tissue. These issues were investigated with and without the presence of Gd ions.

Sensitivities of T2 and T1ρ towards tissue degradation without the presence of Gd

T2 in articular cartilage can be influenced strongly by the dipolar interaction due to the anisotropic motion of water molecules associated with collagen fibrils [14]. It is interesting to observe that T1ρ in BNC is also orientation dependent when the spin-lock field is less than 1 kHz (although it is to a less extent compared to T2 anisotropy). This result implies the existence of weak residual dipolar interactions in BNC under weak spin-locked fields. When the spin-lock field is stronger than 2 kHz, a minimization of the dipolar interaction [33] eliminates the orientational difference of the cartilage specimen in the B0, resulting in a nearly constant T1ρ.

Since T2 is known to be sensitive to both tissue orientation and PG concentration [26, 39, 40], T2 has been used extensively in cartilage MRI. However, in clinical MRI, the reliability of detecting of cartilage lesions using T2 has been inconsistent [41, 42]. One major problem is the depth-dependent T2 anisotropy in articular cartilage [14]. Since most human joints lack any simple geometric shape, it is not possible to orient a patient in the magnet such that the influence of dipolar interaction for the entire joint tissue is uniform. Consequently, T2 values in human MRI are influenced not only by the health status of cartilage but also by tissue orientation in the MRI magnet. It is clear from this project that with a sufficient spin-lock field of 1 kHz or higher, the dipolar interaction in cartilage can be minimized in T1ρ measurements. We can therefore conclude that when the specimen orientation is controlled, T2 and T1ρ both have excellent sensitivity toward cartilage degradation. Because the T2 pulse sequence does not have a spin-lock pulse, the rf power deposition on the tissue in T2 imaging is less than in the T1ρ case, which is a unique advantage in T2 imaging. When the specimen orientation is unknown or cannot be controlled, i.e., human in vivo MRI, T1ρ is a more useful parameter than T2 due to its insensitivity to fibril orientation.

In addition, even at the magic angle, in which the residual dipolar interaction is largely reduced, T1ρ relaxation time is longer than T2. A longer relaxation time is always a welcome feature in clinical MRI since imaging protocols commonly have a long echo time, i.e., less attenuation of the available signal enables improved visualization of the specimen in any intensity based MRI.

Sensitivities of T2 and T1ρ towards tissue degradation in the presence of Gd ions

The situation is entirely different with the presence of Gd ions in the tissue. First, in contrast to a significant increase of up to 80% as with tissues containing no Gd, T1ρ decreases in trypsin-degraded specimens, likely caused by the influx of additional Gd ions to the PG-reduced tissue. Second, T2 becomes insensitive to tissue degradation in the presence of Gd ions, suggesting the paramagnetic Gd-DTPA2− ions dominate the relaxation processes, which mask the effect of dipolar interaction. In fact, if T1ρ images with and without Gd are both available, the difference between these two T1ρ images might be a sensitive indicator of cartilage health. This is because T1ρ is consistently more sensitive to the presence of Gd-DTPA2− in PG degraded specimens than in native specimens, i.e., the black columns in Fig 5 (which equal to “T1ρ-native – T1ρ-native-Gd”) are always much smaller than the gray columns (which equal to “T1ρ-degraded – T1ρ-degraded-Gd”). Please note that the use of Gd contrast agent should be limited to its necessity. If Gd ions were being administrated into patients (like in the dGEMRIC protocol), however, a double T1ρ protocol would be more advantageous than a proper dGEMRIC protocol that requires two T1 scans, since T1ρ-before has its own clinical significance but T1-before does not.

Conclusions

In this project, both T2 and T1ρ relaxation times at both 0° and the magic angle were studied in native and trypsin-degraded BNC specimens, with and without the presence of 1 mM Gd-DTPA2. To the best of our knowledge, this was the first µMRI T2 and T1ρ project of bovine nasal cartilage with full awareness of fibril orientation. Native perpendicular specimens demonstrated significant T1ρ dispersion at 0° and lesser dispersion at the magic angle while native parallel specimens exhibited less anisotropic change of T1ρ dispersion due to fibril axes being parallel with the rotational axis regardless of rotational angle. We have shown that T1ρ values are very sensitive to PG loss regardless of specimen orientation with respect to the magnet field B0. By comparison, the sensitivity of T2 measurements relative to PG loss was dependant upon fibril orientation and exhibited greater sensitivity at the magic angle than 0°. Additionally, the presence of 1 mM Gd-DTPA2− reduced the sensitivity of both T2 and T1ρ toward cartilage degradation.

Acknowledgments

Yang Xia is grateful to the National Institutes of Health for the R01 grants (AR 045172 and AR 052353). The authors thank C Roy Inc (Yale, MI, USA) for providing BNC tissue, Dr. Shaokuan Zheng (Oakland University) for helping with the imaging protocols, Dr Jianhua Yin (Oakland University) for providing the expertise in the biochemical protocol, Ms Janelle Spann (Michigan Resonance Imaging, Rochester Hills, Michigan) for providing the contrast agent, Mr Farid Badar (Oakland University) for helpful discussions, Ms Carol Searight and Mr David Kahn (Oakland University) for editorial comments on the manuscript.

Grant Support: NIH R01 grants (AR 45172, AR 52353)

References

  • 1.Maroudas A. Biophysical chemistry of cartilaginous tissues with special reference to solute and fluid transport. Biorheol. 1975;12:233–248. doi: 10.3233/bir-1975-123-416. [DOI] [PubMed] [Google Scholar]
  • 2.Slowman SD, Brandt KD. Composition and glycosaminoglycan metabolism of articular cartilage from habitually loaded and habitually unloaded sites. Arthritis Rheumatism. 1986;29:88–94. doi: 10.1002/art.1780290112. [DOI] [PubMed] [Google Scholar]
  • 3.Venn M, Maroudas A. Chemical composition and swelling of normal and osteoarthrotic femoral head cartilage. I. Chemical composition. Anna Rheumatic Dis. 1977;36:121. doi: 10.1136/ard.36.2.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Kim DK, Ceckler TL, Hascall VC, Calabro A, Balaban RS. Analysis of water-macromolecule proton magnetization transfer in articular cartilage. Magn Reson Med. 1993;29:211–215. doi: 10.1002/mrm.1910290209. [DOI] [PubMed] [Google Scholar]
  • 5.Bacic G, Liu KJ, Goda F, Hoopes PJ, Rosen GM, Swartz HM. MRI contrast enhanced study of cartilage proteoglycan degradation in the rabbit knee. Magn Reson Med. 1997;37:764–768. doi: 10.1002/mrm.1910370520. [DOI] [PubMed] [Google Scholar]
  • 6.Gray ML, Burstein D, Xia Y. Biochemical (and Functional) Imaging of Articular Cartilage. Semin Musculoskelet Radiol. 2001;5:329–344. doi: 10.1055/s-2001-19043. [DOI] [PubMed] [Google Scholar]
  • 7.Bashir A, Gray ML, Burstein D. Gd-DTPA2-as a measure of cartilage degradation. Magn Reson Med. 1996;36:665–673. doi: 10.1002/mrm.1910360504. [DOI] [PubMed] [Google Scholar]
  • 8.Burstein D, Velyvis J, Scott KT, Stock KW, Kim YJ, Jaramillo D, Boutin RD, Gray ML. Protocol issues for delayed Gd(DTPA)(2-)-enhanced MRI (dGEMRIC) for clinical evaluation of articular cartilage. Magn Reson Med. 2001;45:36–41. doi: 10.1002/1522-2594(200101)45:1<36::aid-mrm1006>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  • 9.Tiderius C, Olsson L, Leander P, Ekberg O, Dahlberg L. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) in early knee osteoarthritis. Magn Reson Med. 2003;49:488–492. doi: 10.1002/mrm.10389. [DOI] [PubMed] [Google Scholar]
  • 10.Xia Y, Zheng S, Bidthanapally A. Depth-dependent Profiles of Glycosaminoglycans in Articular Cartilage by µMRI and Histochemistry. J Magn Reson Imaging. 2008;28:151–157. doi: 10.1002/jmri.21392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Zheng S, Xia Y. The impact of the relaxivity definition on the quantitative measurement of glycosaminoglycans in cartilage by the MRI dGEMRIC method. Magn Reson Med. 2010;63:25–32. doi: 10.1002/mrm.22169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Reddy R, Insko EK, Noyszewski EA, Dandora R, Kneeland JB, Leigh JS. Sodium MRI of human articular cartilage in vivo. Magn Reson Med. 1998;39:697–701. doi: 10.1002/mrm.1910390505. [DOI] [PubMed] [Google Scholar]
  • 13.Shapiro EM, Borthakur A, Dandora R, Kriss A, Leigh JS, Reddy R. Sodium visibility and quantitation in intact bovine articular cartilage using high field 23Na MRI and MRS. J Magn Reson. 2000;142:24–31. doi: 10.1006/jmre.1999.1932. [DOI] [PubMed] [Google Scholar]
  • 14.Xia Y. Relaxation anisotropy in cartilage by NMR microscopy (µMRI) at 14µm resolution. Magn Reson Med. 1998;39:941–949. doi: 10.1002/mrm.1910390612. [DOI] [PubMed] [Google Scholar]
  • 15.Xia Y. Magic-angle effect in magnetic resonance imaging of articular cartilage: a review. Investigative Radiol. 2000;35:602. doi: 10.1097/00004424-200010000-00007. [DOI] [PubMed] [Google Scholar]
  • 16.Mlynarik V, Mosher TJ, Smith HE, Dardzinski B. Magic angle effect in articular cartilage. Am J Roentgenol. 2002;178:1287. doi: 10.2214/ajr.178.5.1781287. [DOI] [PubMed] [Google Scholar]
  • 17.Duvvuri U, Kudchodkar S, Reddy R, Leigh JS. T1rho relaxation can assess longitudinal proteoglycan loss from articular cartilage in vitro. Osteoarthritis Cartilage. 2002;10:838–844. doi: 10.1053/joca.2002.0826. [DOI] [PubMed] [Google Scholar]
  • 18.Regatte RR, Akella SVS, Lonner JH, Kneeland JB, Reddy R. T1rho relaxation mapping in human osteoarthritis (OA) cartilage: Comparison of T1rho with T2. J Magn Reson Imaging. 2006;23:547–553. doi: 10.1002/jmri.20536. [DOI] [PubMed] [Google Scholar]
  • 19.Li X, Ma BC, Link TM, Castillo DD, Blumenkrantz G, Lozano J, Carballido-Gamio J, Ries M, Majumdar S. In vivo T1rho and T2 mapping of articular cartilage in osteoarthritis of the knee using 3 T MRI. Osteoarthritis Cartilage. 2007;15:789–797. doi: 10.1016/j.joca.2007.01.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Bolbos RI, Link TM, Ma BC, Majumdar S, Li X. T1rho relaxation time of the meniscus and its relationship with T1rho of adjacent cartilage in knees with acute ACL injuries at 3 T. Osteoarthritis Cartilage. 2009;17:12–18. doi: 10.1016/j.joca.2008.05.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Fullerton GD, Cameron IL, Ord VA. Orientation of tendons in the magnetic field and its effect on T2 relaxation times. Radiol. 1985;155:433. doi: 10.1148/radiology.155.2.3983395. [DOI] [PubMed] [Google Scholar]
  • 22.Peto S, Gillis P, Henri VP. Structure and dynamics of water in tendon from NMR relaxation measurements. Biophys J. 1990;57:71–84. doi: 10.1016/S0006-3495(90)82508-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Rubenstein JD, Kim JK, Morava-Protzner I, Stanchev PL, Henkelman RM. Effects of collagen orientation on MR imaging characteristics of bovine articular cartilage. Radiol. 1993;188:219–226. doi: 10.1148/radiology.188.1.8511302. [DOI] [PubMed] [Google Scholar]
  • 24.Mosher TJ, Smith H, Dardzinski BJ, Schmithorst VJ, Smith MB. MR Imaging and T2 Mapping of Femoral Cartilage: In Vivo Determination of the Magic Angle Effect. Am J Roentgen. 2001;177:665–669. doi: 10.2214/ajr.177.3.1770665. [DOI] [PubMed] [Google Scholar]
  • 25.Alhadlaq H, Xia Y, Moody JB, Matyas J. Detecting Structural Changes in Early Experimental Osteoarthritis of Tibial Cartilage by Microscopic MRI and Polarized Light Microscopy. Ann Rheum Dis. 2004;63:709–717. doi: 10.1136/ard.2003.011783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Zheng S, Xia Y. Multi-components of T2 relaxation in ex vivo cartilage and tendon. J Magn Reson. 2009;198:188–196. doi: 10.1016/j.jmr.2009.02.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Mekela HI, Grohn OHJ, Kettunen MI, Kauppinen RA. Proton exchange as a relaxation mechanism for T1 in the rotating frame in native and immobilized protein solutions. Biochem Biophys Res Communicat. 2001;289:813–818. doi: 10.1006/bbrc.2001.6058. [DOI] [PubMed] [Google Scholar]
  • 28.Duvvuri U, Goldberg AD, Kranz JK, Hoang L, Reddy R, Wehrli FW, Wand AJ, Englander SW, Leigh JS. Water magnetic relaxation dispersion in biological systems: The contribution of proton exchange and implications for the noninvasive detection of cartilage degradation. Proc Natl Acad Sci U S A. 2001;98:12479–12484. doi: 10.1073/pnas.221471898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Regatte RR, Akella SVS, Borthakur A, Kneeland JB, Reddy R. Proteoglycan Depletion-Induced Changes in Transverse Relaxation Maps of Cartilage: Comparison of T2 and T1rho. Acad Radiol. 2002;9:1388–1394. doi: 10.1016/s1076-6332(03)80666-9. [DOI] [PubMed] [Google Scholar]
  • 30.Akella SVS, Regatte RR, Borthakur A, Kneeland JB, Leigh JS, Reddy R. T1rho MR Imaging of the Human Wrist in Vivo. Acad Radiol. 2003;10:614–619. doi: 10.1016/s1076-6332(03)80079-x. [DOI] [PubMed] [Google Scholar]
  • 31.Mlynarik V, Szomolanyi P, Toffanin R, Vittur F, Trattnig S. Transverse relaxation mechanisms in articular cartilage. J Magn Reson. 2004;169:300–307. doi: 10.1016/j.jmr.2004.05.003. [DOI] [PubMed] [Google Scholar]
  • 32.Li X, Cheng J, Lin K, Saadat E, Bolbos RI, Jobke B, Ries MD, Horvai A, Link TM, Majumdar S. Quantitative MRI using T1rho and T2 in human osteoarthritic cartilage specimens: correlation with biochemical measurements and histology. Magn Reson Imaging. 2011;29:324–334. doi: 10.1016/j.mri.2010.09.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Akella SVS, Regatte RR, Wheaton AJ, Borthakur A, Reddy R. Reduction of residual dipolar interaction in cartilage by spin-lock technique. Magn Reson Med. 2004;52:1103–1109. doi: 10.1002/mrm.20241. [DOI] [PubMed] [Google Scholar]
  • 34.Stanisz GJ, Henkelman RM. Gd-DTPA relaxivity depends on macromolecular content. Magn Reson Med. 2000;44:665–667. doi: 10.1002/1522-2594(200011)44:5<665::aid-mrm1>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  • 35.Henkelman RM, Stanisz GJ, Menezes N, Burstein D. Can MTR be used to assess cartilage in the presence of Gd-DTPA2-? Magn Reson Med. 2002;48:1081–1084. doi: 10.1002/mrm.10322. [DOI] [PubMed] [Google Scholar]
  • 36.Nieminen MT, Menezes NM, Williams A, Burstein D. T2 of articular cartilage in the presence of Gd-DTPA2. Magn Reson Med. 2004;51:1147–1152. doi: 10.1002/mrm.20083. [DOI] [PubMed] [Google Scholar]
  • 37.Richmon JD, Sage A, Van Wong W, Chen AC, Sah RL, Watson D. Compressive biomechanical properties of human nasal septal cartilage. Am J Rhinol. 2006;20:496–501. doi: 10.2500/ajr.2006.20.2932. [DOI] [PubMed] [Google Scholar]
  • 38.Xia Y, Zheng S, Szarko M, Lee J. Anisotropic properties of bovine nasal cartilage. Microsc Res Tech. 2011 doi: 10.1002/jemt.21058. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Xia Y, Farquhar T, Burton-Wurster N, Vernier-Singer M, Lust G, Jelinski L. Self-diffusion monitors degraded cartilage. Arch Biochem Biophys. 1995;323:323–328. doi: 10.1006/abbi.1995.9958. [DOI] [PubMed] [Google Scholar]
  • 40.Zheng S, Xia Y, Bidthanapally A, Badar F, Ilsar I, Duvoisin N. Damages to the extracellular matrix in articular cartilage due to cryopreservation by microscopic magnetic resonance imaging and biochemistry. Magn Reson Imaging. 2009;27:648–655. doi: 10.1016/j.mri.2008.10.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Burstein D, Gray ML. Is MRI fulfilling its promise for molecular imaging of cartilage in arthritis? Osteoarthritis Cartilage. 2006;14:1087–1090. doi: 10.1016/j.joca.2006.07.001. [DOI] [PubMed] [Google Scholar]
  • 42.Xia Y. Resolution 'scaling law' in MRI of articular cartilage. Osteoarthritis Cartilage. 2007;15:363–365. doi: 10.1016/j.joca.2006.12.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

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