Dynamic contrast enhanced-magnetic resonance imaging study of the nutrition pathway for lumbar...

SCIENTIFIC ARTICLE

Dynamic contrast enhanced-magnetic resonanceimaging study of the nutrition pathway for lumbar

intervertebral disk cartilage of normal goatsos4_123 106..112

Heng Du MD1, Shao-hui Ma MD2, Min Guan MD2, Bo Han PhD3, Guang-fu Yang MD3,Ming Zhang MD, PhD2, Miao Liu MD, PhD1

1Departments of Orthopedics and 2Medical Imaging, The First Affiliated Hospital of Xi’an Jiaotong University, and 3Department ofRadiology, Xi’an Gaoxin Hospital, Xi’an, China

Objective: Study of the nutrition pathway for lumbar intervertebral disk cartilage of normal goats.

Methods: Four lumbar intervertebral disks from each of eight 24-month-old goats (32 disks) were studied. After thegoats had been anesthetized, signal intensity changes in the regions of interest (ROI) were observed by dynamic contrastenhanced magnetic resonance scanning. Before and after enhancement at the time points of 0, 5, 10, and 30 mins, and1.0, 1.5, 2.0, 2.5, 3.0, and 3.5 hs, the ROI signal intensity was measured, and the time-signal intensity curve and peak timesanalyzed.

Results: Signal intensity in the vertebral bodies reached a peak at 0 min and decreased quickly thereafter. Signalintensity in the cartilage endplate zones reached the first peak at 30 mins and then went down slightly before increasingto a second peak at 2 hs. Signal intensity in the nuclei pulposus was negative within 5 mins, increased slowly to a peak at2 hs, and declined thereafter.

Conclusion: Nutrient metabolism of the lumbar intervertebral disks of normal goats occurs mainly through thecartilage end-plate pathway.

Key words: Gadolinium diethylenetriamine penta-acetic acid; Goats; Intervertebral disk; Magnetic resonanceimaging

Introduction

Protrusion of the nucleus pulposus, facet joint degen-eration, spinal instability, and spinal canal stenosis causedby disk degeneration often lead to lumbar and leg painand cause physical and psychological suffering and eco-nomic burdens for affected patients1,2. Many studies haveshown that disk degeneration is related to reduced supplyof nutrition, apoptosis imbalance, changes in the activityof matrix enzymes, biomechanics and autoimmunereactions3–6.

Reduction in supply of nutrient substances has beenconsidered to be the main factor resulting in eventualdevelopment of disk degeneration7. Numerous studies

have shown that nutrition of intervertebral disks isobtained mainly through the endplates, and that there is aclose relationship between degeneration of endplates andthat of intervertebral disks8,9.

Tissue engineering and gene therapy studies of the diskarea have become keys to investigating how intervertebraldisks obtain nutrients. However, understanding of thecomplexities of disk nutrition in humans is notenough10,11. Therefore, studies of disk nutrition in animalsmay help us to learn more about this topic.

However, after unilaterally obstructing the nutritionpathway for endplates in dogs for 70 weeks, Hutton et al.found that, in most cases, degeneration of the interverte-bral disks had not occurred12. Therefore, further study ofthe relationship between the nutrition pathway of the car-tilage endplates of intervertebral disks and their degenera-tion is necessary. Because it requires dissection of thedogs’ lumbar transverse arteries, it is not feasible to estab-lish a model of bilateral blocking of the nutrition of theend-plate. Therefore, it became necessary to choose a newexperimental animal for studying the nutrition pathway

Address for correspondence Heng Du, MD, Department ofOrthopedics, The First Affiliated Hospital of Xi’an JiaotongUniversity, School of Medicine, 277 Yanta West Road, Xi’an, China710061 Tel: 0086-29-85323935; Fax: 0086-29-85252580; Email:[email protected]

Received: 7 December 2010; accepted 24 January 2011DOI: 10.1111/j.1757-7861.2011.00123.x

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© 2011 Tianjin Hospital and Blackwell Publishing Asia Pty Ltd 106

for lumbar intervertebral disk cartilage and further estab-lishing animal models for researching the relationshipbetween nutrition and disk degeneration.

Dynamic contrast-enhanced MRI (DCE-MRI) scansare a non-invasive and reproducible method that has beenused to study the nutrition mechanism of disks13. UsingDCE-MRI techniques, Rajasekaran et al. observed lumbarintervertebral disks in 150 individuals continuously for24 hs to study the diffusion process of contrast agents invarious parts of the disks14. Through non-invasive studyby DCE-MRI of normal goat lumbar disks, the purpose ofthe present research was to study the nutrition pathway ofnormal goat vertebral endplates.

Materials and methods

Experimental animalsEight healthy adult goats (average age, 24 � 2.1 months,

average weight,41.3 � 5.1 kg) were provided by the AnimalCenter of the Medical School of Xi’an Jiaotong University.The sample goats were fed by members of the Xi’an Jiao-tong University Animal Experimentation Committee for 2weeks under standard rearing conditions. The protocolsfor all animals used in the current study were approved bythe Xi’an Jiaotong University Animal ExperimentationCommittee and performed under the Xi’an Jiaotong Uni-versity Guidelines for Animal Experimentation.

Instruments and methodsThe Philips Intera Achieva 1.5 T MRI system dual-

gradient (Best, the Netherlands) was used in this experi-ment. The animals were fasted for 24 hs preoperativelyand atropine 0.03–0.05 mg/kg was given by i.m. injection20–30 mins before surgery. After Sumianxin (a combina-tion of haloperidol and dihydroetorphine, 0.3 ml/kg bodyweight) had been given to the sample goats by i.m. injec-tion for basic anesthesia, continuous ear vein infusion ofpropofol (2 mg/kg) was given to maintain adequate anes-thesia, and tracheal intubation performed. A syringe con-taining 50 ml of pure water was placed in the lumbardorsal region as a water model. A SENSE body coil formeasuring phase resonance was wrapped on the goats atthe lumbar level with the goats in a lateral position and thecaudal end applied first and was used for surface location.Firstly, T2WI-TSE-SPAIR (repetition time/ echo time[TR/TE] = 3500 ms/60 ms, slices of thickness/gab =4.0 mm/0.6 mm, scan time 3 mins 31 secs) were scanned.Next, after excluding disk degeneration deformity in thescan field region, sagittal T1-TSE-SPIR (TR/TE = 400 ms/7.8 ms, slice thickness/gab = 4.0 mm/0.6 mm, scan time 3mins 31 seconds) were scanned. After line DCE-MRI hadbeen performed, gadobenate dimeglumine (Gd-BOPTA)

(ionic, molecular weight 1058.17), which enhances con-trast, was given by ear vein catheter injection (dose0.3 mmol/kg). Taking the time of contrast media injectionas 0 min, and the scanning sequence for the sagittalT1-TSE-SPIR at 0 min, 5 mins, 10 mins, 30 mins, 1.0 h,1.5 hs, 2.0 hs, 2.5 hs, 3.0 hs, and 3.5 hs, the variables werethe same as for the non-enhanced scan. The whole processof the experiment lasted for 5–7 hs.

AnalysisAfter scanning, the median sagittal lumbar level was

selected. Regions of interest (ROI) were selected corre-sponding to five regions, namely the upper and lowervertebral bodies, the upper and lower cartilage endplatezones, and the nuclei pulposus (Fig. 1). In accordancewith the shape of the observation site, the ROI of thevertebral and endplate zones selected the rectangle, andthe numbers of pixels were 80 and 12, respectively. Theoval was selected for the ROI of the nucleus area and thenumber of pixels was 16. The rectangular ROI was placedin the water mold area and the number of pixels wasaround 100. Attempts were made to avoid a partial volumeeffect when selecting these ROI. Within the same windowwidth and window level, the six ROI signal intensityvalues for each vertebral disk, shown clearly under differ-ent time scan fields, were measured and recorded.

Statistical analysisSPSS software 13.0 (SPSS, Chicago, IL, USA) was used

for statistical analysis; the mean � SD was used to show

Figure 1 Region of interest were selected corresponding to fiveregions, namely the upper and lower vertebral bodies, upper andlower cartilage endplate zones, and nuclei pulposus.

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dispersion of the data. By analyzing the signal intensitychanges of the water model, it was possible to confirm thatthe measured data was in a stable magnetic field, whichensured that the research data was statistically significant.

Results

Nucleus pulposusIn the scan fields, the 32 nuclei pulposus of eight goats

were all shown clearly and no malformation of them wasidentified. Lumbar disks with degeneration in the nucleipulposus were sampled in this study.

Observations on the morphology of normal goatvertebral disks

The T2WI-TSE-SPAIR sequences showed uniformlyhigh signals of the nuclei pulposus, which are oval inshape. The peripheral fibroid annuli and cartilage end-plates showed low signals (Fig. 2A). The normal disks

could be seen in the T1-TSE-SPIR sequences, andwere similar to those displayed in the T2-TSE-SPAIRsequences. Low signal area bands, which are cartilage end-plate zones, could be seen between the vertebrae andnuclei pulposus (Fig. 2B). After MRI scan with injectionof Gd-BOPTA, the T1-TSE-SPIR sequences in the sagittalplane showed no enhanced signals on the nuclei pulposus,while the vertebral bodies were significantly enhanced,and the transverse lumbar arteries could be seen (Fig. 2C).

Dynamic enhancement changes in each regionAfter injecting Gd-BOPTA, the signal intensity on the

upper and lower vertebra bodies reached a peak at 0 min,and then declined rapidly until beginning to increaseagain at 1 h to a second peak, which was lower than thefirst one, at 2 hs, and thereafter gradually decreased. Thechange trend of the signal intensity on the upper andlower vertebral bodies was consistent. The signal intensityon the upper and lower cartilage endplate zones slowly

A B C

Figure 2 Observation of the morphology of normal goat vertebral disks (A) T2-TSE-SPAIR sequence: the nuclei pulposus show high intensity,and the peripheral fibrous rings and cartilage endplates low intensity. (B) T1-TSE-SPIR sequence: the vertebral disks show isointensity, and thenuclei pulpous and fibroid annuli are difficult to e distinguish from each other. (C) T1-TSE-SPIR sequence after the injection of Gd-BOPTA: thenuclei pulposus are not enhanced, whereas the vertebral bodies are significantly enhanced. The transverse lumbar arteries can be seenentering the vertebrae.

108 H Du et al., Nutrition pathway for disk cartilage


increased to a moderate peak at 10 mins. After decreasingslightly, it then rapidly increased, reaching a second peakat 2 hs. The curves of the upper and lower cartilage end-plate zones did not overlap and the signal intensity on thearea under the cartilage endplates was higher than the

superior endplate zones. The signal intensity on the nucleipulposus appeared as a negative value at 5 mins, and thenslowly increased, the increase acceleratingt at 30 mins, andreaching a peak at 2 hs, after which it gradually declined(Figs 3A–I, 4).

A B C

F

ED

G H JI

Figure 3 Enhanced T1-SPIR sequences showing the dynamic MR changes at different time points (A) pre-injection of Gd-BOPTA; (B) at 0 mins;(C) at 5 mins; (D) at 10 mins; (E) at 30 mins; (F) at 1.0 h; (G) at 1.5 hs; (H) at 2.0 hs; (I) at 2.5 hs; and (J) at 3 hs.

Figure 4 The time-signal intensity of five ROIs. EPZ, end plate zone; NP, nucleus pulposus; VB, vertebral body.



Discussion

This research employed DCE-MRI techniques to studythe nutrition pathway of normal goat vertebral endplates.The goats tolerated the procedures well. This experimentproved that the lumbar vertebral transverse arteries ofgoats enter the vertebrae at their center, which provides anexperimental basis for establishing animal models ofbilateral blocking of the nutritional pathway to the end-plates in goats. In this experiment we used DCE-MRItechniques to study the metabolic process and character-istics of Gd-BOPTA in goat lumbar intervertebral disksrelatively completely. We propose that nutrient metabo-lism of the lumbar intervertebral disks of normal goatsoccurs mainly through cartilage end-plate pathways.

The earliest study on the nutritional pathway of theintervertebral disk was carried out by infusing fluorescentor radioactive markers into animal disks, the markersbeing found to permeate the disks from the peripheraltissues of the vertebral bodies and annuli fibrosis. In thelast few years, some studies have applied MRI techniquesin studying the nutrition path of disks15,16. DCE-MRImeasures the speed of permeation and quantity ofparamagnetic contrast agents in the disks, reflecting thenutrition diffusion process. Because the method can beconducted in vivo, it has the advantages of being repro-ducible and noninvasive, as well as allowing quantitativeanalysis and producing practical results.

We chose goats as an animal model for studying thenutritional pathway of intervertebral disks in vivo. Inorder to be sure that the model was comparable withhumans in respect to the anatomy of the intervertebraldisk and its degeneration process, we sought to satisfy thefollowing requirements. Firstly, the histologic characteris-tics of degeneration and morphologic characteristics ofdisk herniation should be reproduced. Secondly, themodel should be reproducible. Thirdly, the anatomicaland physiological characteristics of the selected animalsshould be as similar to humans as possible. The idealdegeneration model would use primates (monkeys),because they are most similar to humans17. With theirclose evolutionary and genetic relationship with humans,monkeys have lumbar disks which have similar biochemi-cal and mechanical properties to those of humans. There-fore, monkeys are ideal animals for establishing anintervertebral disk degeneration model18. However, eco-nomic and legal factors limit the choice of monkeys. Overthe last 10 years, fairly big animals such as the pig, goatand dog have been selected for studying disk herniationand degeneration19,20. Besides their advantages of havinggentle characters, being easy to feed and control, costingrelatively little to obtain and feed, being large in size, and

being suitable for obtaining repeated blood, urine andtissue samples, goats can tolerate having DCE-MRI per-formed during long periods of anesthesia, and theimaging data are clear and easy to distinguish. The presentexperiment lasted 5 to 7 hs, and the goats showed goodtolerance. Twenty-four-month-old goats, which corre-spond to adolescents, were selected for this study, becauseat this age their intervertebral disk structure is stable, andhas not begun to degenerate.

The time-signal intensity curves of goat’s vertebralbodies are similar to those of humans13,14. There are twopathways by which MR contrast agent reaches vertebralbodies after it been administered i.v.: starting from abranch of the spinal artery to the posterior center of thevertebral bodies, and starting from branches of thelumbar and intercostal arteries to their anterior lateralaspects. After entering the vertebral bodies the vessels aredistributed horizontally into their centers. Branch-liketributaries spread radially in upper and lower directionsafter anastomosing with each other, and extend to bothends of the vertebral bodies. Then they anastomose at theendplates and inferiorly, forming vascular loops21. There-fore, once the contrast agent has arrived at the vertebralbodies, the nuclear MR signal intensity reaches a peakimmediately and falls off gradually as its plasma concen-tration changes. One h later, the curve starts to increaseagain, reaching a second peak at 2 hs, which might be dueto the mixing of contrast agent with metabolic products ofthe nuclei pulposus and reaching the vertebral bodies in areverse manner via their endplates. The second peak issignificantly lower than the first one.

The nutrition of the goat lumbar endplate zones isinfluenced by the anatomical structure and metabolism ofthe nuclei pulposus. The vessels of the vertebral bodiesanastomose to vascular loops at the endplates and inferiorto them, then extend to the cartilage endplates and formvascular buds, the number determining the permeabilityof the cartilage endplates22. In the central area of the car-tilage endplates, the vascular buds are enlarged andoverlap, so their contact surface is large and the perme-ability high. However, because the peripherally locatedvascular buds are separate loops, their contact surface issmaller and permeability lower. By diffusion, the nutri-tional ingredients in capillaries permeate the hyaline car-tilage endplates (the convection mechanism is relativelyminor), and then reach the extracellular matrix of theintervertebral disks. After infusion of contrast agent, thetime-signal intensity curve of the endplates increasesteadily, reaching the first peak within 10 mins, thendecreasing slightly. One h later the curve rises quickly andreaches a second peak at 2 hs, then declines rapidly. Thesecond peak is significantly higher and steeper than the



first one. The reason for the curve changing in this waymight be that the small blood vessel diameter of the vas-cular buds at the vertebral and cartilage endplates resultsin a decrease in the speed at which contrast agent entersthe vertebral sinuses. Accordingly, the concentration andrate of increase of contrast agent at the endplates are lowerthan at the vertebral bodies. The time-signal intensitycurve at endplate rises slightly and reaches the smallerpeak at 10 mins. Later, because of a delay in diffusion andrapid decline in plasma concentration, the concentrationof contrast decreases at the endplates. Therefore, the rateof change of the curve slows down, while maintaining ahigher level. With contrast agent entering in the nucleipulposus and some of the contrast agent being metabo-lized, the curve rises again 1 h later and reaches a dynamicequilibrium to form the second peak. After this, contrastagent entering the nuclei pulposus decreases markedlydueto it being increasingly metabolized, the curve begins todecline.

In addition, the time-signal intensity curve of the nucleipulposus below the horizontal axis within 10 mins; themechanism for this is hard to define. A possible reason isthat the vertebral bodies and endplates are intensified in10 mins and the molecular concentration of gadodiamidereaches a certain level in them. However, the molecularconcentration of gadodiamide in the nuclei pulposus atthis stage is rather low. The enhancement effect of contrastagent in the vertebral bodies and endplates may produce“negative interference” on the contrast agent in the nucleipulposus. This would result in a decline in the signalintensity of the nuclei pulposus. The mechanism needs tobe further studied. After i.v. injection of Gd-BOPTA, rapidenhancement occurs for 30 mins, the intensity reaching apeak at 2 hs. It then declines gradually, still being above thebaseline at 4 hs. The increase in nucleus pulposus intensityoccurs after the dispersal peak of the endplates hasoccurred, which indicates that the nutritional ingredientsare obtained mainly by dispersal from the endplates. Sincethe metabolism of the nuclei pulposus is slow, the inten-sity there is still above the baseline at 4 hs, although thereis a clear trend to decline. These data suggest that obtain-ing of nutrition from the nucleus pulposus is a slowprocess.

The time-intensity curve of the nuclei pulposus in goatsis similar to that reported by Rajasekaran et al., whostudied the dispersal of nutritional ingredients in humanintervertebral disks with MRI13,14. This shows that thenutrition pathway of goat intervertebral disks is similar tothat of humans. However, in contrast to the time-intensitycurve obtained by Rajasekaran et al., in the present experi-ment the peak of the nuclei pulposus occurred at 2 hs(earlier than in Rajasekaran et al.’s study), after which it

immediately began to decrease. There are two possiblereasons for this difference. Firstly, the cartilage endplates(cell layers) of goats are thinner than those of humans andthe nuclei pulposus are notably smaller, so the contrastagent would more easily saturate them and reach its peakearlier. Secondly, the contrast agent used in the presentexperiment was Gd-BOPTA, which contains phenoxy andis a lipophilic aromatic compound. BecauseGd-BOPTAbinds to plasma proteins, especially albumin, its clearancerate is significantly faster than that of other MRI contrastagents23. De Haën et al. indicated that the benzene ringplays a regulatory role in Gd-BOPTA metabolism,enabling liver cells to absorb the Gd-BOPTA moleculeselectively and excrete it via the biliary tree24. The absorp-tion mechanism is the same as for bilirubin metabolism;that is absorption and excretion occur through multi-specific organic anion transport channels in the liver cellmembranes. It has been suggested that Gd-BOPTA may berelated to the metabolism of proteoglycan with higherfixed negative charge in the nucleus pulposus, but furtherstudies are needed for clarifying these mechanisms.

In this study a water phantom was used to rectify mea-surement of signal intensity, because signal intensity oftissues can be influenced by the stability of MR equip-ment. The goats were under anesthesia and coils werewrapped around their bodies. Because the experimentlasted several hs, body temperature and sweat would havecaused some interference to the magnetic field. Therefore,a water phantom was necessary to enable calculation ofexact values.

In conclusion, the present experiment studies theprocess of nutritional ingredients entering, and metabolicwastes being excreted from, goat intervertebral disks. Ithas clarified the nutrition pathway of goat lumbar inter-vertebral disk cartilage end-plates and its significance. Thecurrent study provides a basis for the establishment of ananimal model for bilateral blocking of the nutritionalpathway of the goat’s endplates and future related researchon the relationship between nutrition and metabolism inthis region.

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