Deep Cartilage Research Articles

Quantitative three-dimensional ultrashort echo time cones imaging of the knee joint with motion correction.

Knee degeneration involves all the major tissues in the joint. However, conventional MRI sequences can only detect signals from long T2 tissues such as the superficial cartilage, with little signal from the deep cartilage, menisci, ligaments, tendons and bone. It is highly desirable to develop new sequences that can detect signal from all major tissues in the knee. We aimed to develop a comprehensive quantitative three-dimensional ultrashort echo time (3D UTE) cones imaging protocol for a truly "whole joint" evaluation of knee degeneration. The protocol included 3D UTE cones actual flip angle imaging (3D UTE-Cones-AFI) for T1 mapping, multiecho UTE-Cones with fat suppression for T2 * mapping, UTE-Cones with adiabatic T1ρ (AdiabT1ρ ) preparation for AdiabT1ρ mapping, and UTE-Cones magnetization transfer (UTE-Cones-MT) for MT ratio (MTR) and modeling of macromolecular proton fraction (f). An elastix registration technique was used to compensate for motion during scans. Quantitative data analyses were performed on the registered data. Three knee specimens and 15 volunteers were evaluated at 3T. The elastix motion correction algorithm worked well in correcting motion artifacts associated with relatively long scan times. Much improved curve fitting was achieved for all UTE-Cones biomarkers with greatly reduced root mean square errors. The averaged T1 , T2 *, AdiabT1ρ , MTR and f for knee joint tissues of 15 healthy volunteers were reported. The 3D UTE-Cones quantitative imaging techniques (ie, T1 , T2 *, AdiabT1ρ , MTR and MT modeling) together with elastix motion correction provide robust volumetric measurement of relaxation times, MTR and f of both short and long T2 tissues in the knee joint.

Potential predictive value of axial T2 mapping at 3 Tesla MRI in patients with untreated patellar cartilage defects over a mean follow-up of four years

The objective was to demonstrate the potential of axial T2 mapping for quantification of untreated early-stage patellar cartilage lesions over time and to assess its capability as a potential predictive marker for future progression. Thirty patients (mean age, 36.7±11.1 years; 16 males), with early-stage patellar cartilage defects (≤ICRS grade 2) at baseline and no treatment during follow up (4.0±1.6 years) were enrolled. Morphological cartilage changes over time were subdivided into a Progression, Non-Progression Group and Regression Group. Quantitative analysis of cartilage defects and healthy reference was performed by means of global and zonal T2 mapping (deep and superficial cartilage T2 values) at both time points. Statistical evaluation included analysis of variance (ANOVA), paired t Test's and ROC analysis. The Progression Group (N=11) had significantly higher global T2 values at baseline (57.4±7.8ms) than patients without (N=17) (40.6±6.9ms) (P<0.01). Furthermore the Non-Progression Group showed only a minor increase in global T2 relaxation times to 43.1±7.9ms (P=0.07) at follow up, whereas in the progression group global (68,7±19ms: P=0.02) and superficial T2 values (65,8±8.2-79.8±24.4ms; P=0.03) increased significantly. T2 values for healthy reference cartilage remained stable. In 2 patients an improvement in ICRS grading was observed (Regression Group) with decreasing T2 values. The ROC analysis showed an area under the curve of 0.92 (95%CI 0.82-1.0). At a cut-off value of 47.15ms, we found a sensitivity of 92% (false-positive rate of 18%) for future progression of cartilage defects. This study provides evidence regarding the possible potential of axial T2 mapping as a tool for quantification and prediction of patellar cartilage defect progression in untreated defects.

Extracting Voxel-Based Cartilage Relaxometry Features in Hip Osteoarthritis Subjects Using Principal Component Analysis.

MRI-based relaxation time measurements provide quantitative assessment of cartilage biochemistry. Identifying distinctive relaxometry features in hip osteoarthritis (OA) might provide important information on regional disease variability. First, to incorporate fully automatic voxel-based relaxometry (VBR) with principal component analysis (PCA) to extract distinctive relaxometry features in subjects with radiographic hip OA and nondiseased controls. Second, to use the identified features to further distinguish subjects with cartilage compositional abnormalities. Cross-sectional. Thirty-three subjects with radiographic hip OA (20 males; age, 50.2 ± 13.3 years) and 55 controls participated (28 males; 41.3 ± 12.0 years). A 3.0T scanner using 3D SPGR, combined T1ρ /T2 , and fast spin echo sequences. Pelvic radiographs, patients' self-reported symptoms, physical function, and cartilage morphology were analyzed. Cartilage relaxation times were quantified using traditional regions of interest and VBR approaches. PCA was performed on VBR data to identify distinctive relaxometry features, and were subsequently used to identify a subgroup of subjects from the controls that exhibited compositional abnormalities. Chi-square and independent t-tests were used to compare group characteristics. Logistic regression models were used to identify the possible principal components (PCs) that were able to predict OA vs. control classification. In T1ρ assessment, OA subjects demonstrated higher T1ρ values in the posterior hip region and deep cartilage layer when compared with controls (P = 0.012 and 0.001, respectively). In T2 assessment, OA subjects exhibited higher T2 values in the posterior hip region (P < 0.001). Based on the PC score classification, 16 subjects without radiographic evidence of OA demonstrated relaxometry patterns similar to OA subjects, and exhibited worse physical function (P = 0.003) and cartilage lesions (P = 0.009-0.032) when compared with the remaining controls. The study identified distinctive cartilage relaxometry features that were able to discriminate subjects with and without radiographic hip OA effectively. 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1708-1719.

Assessment of short-term and mid-term changes of knee cartilage before and after marathon using T2 mapping imaging

Objective Assessment of short-term and mid-term changes of knee cartilage in non-professional long-distance runners before and after marathon using T2 mapping imaging. Methods Twenty-four knee joints of 12 healthy volunteers (5 males and 7 females) who participated in the marathon were examined by 3.0 T MRI one week before the race, within 12 hours after the race and two months after the race, respectively. The age ranged from 21.0 to 37.0 years. Athletes run more than three times a week, and each time was about 30 minutes. From T2 mapping we can obtain T2 value of 6 cartilage subregions of knee joint. Paired t-test was used to compare the T2 values of cartilage before and after the marathon. The comparison between the superficial and deep T2 values of cartilage was performed by independent sample t test. Results T2 mapping imaging showed that the T2 value of the superficial articular cartilage was higher than that of deep articular cartilage in pre-competition, within 12 hours after competition and 2 months follow-up, respectively (t=11.095, 10.385 and 10.102, P 0.05). Except for the MTP-DZ, the T2 value of the remaining cartilage subregions showed a trend of decrease within 12 hours after the competition. There were significant differences in the subregion of MFC-DZ (t=2.110,P 0.05). The T2 values of the LFC-SZ and LFC-DZ were lower than those before the race, with statistical significance (t=2.378, 3.147,P<0.05). Conclusion T2 value could reflect the change process of articular cartilage tissue composition in marathon runners from T2 mapping imaging. Under stress, the changes of superficial T2 value are more significant. The T2 value of knee cartilage can gradually recover to the pre-run level 2 months after running. Key words: Sports medicine; Knee joint; Cartilage; Magnetic resonance imaging; T2 mapping

Patients with Type 2 Diabetes Exhibit a More Mineralized Deep Cartilage Layer Compared with Nondiabetic Controls: A Pilot Study.

To assess differences in biochemical composition of the deep cartilage layer in subjects with type 2 diabetes mellitus (T2DM) and nondiabetic controls using UTE (ultra-short echo time) T2* mapping and to investigate the association of vascular health and UTE T2* measurements. Ten subjects with T2DM matched for age, sex, and body mass index with 10 nondiabetic controls. A 3D UTE sequence with 6 echo times was acquired using 3T magnetic resonance imaging of the knee. For UTE T2* analysis, the deep cartilage layer was segmented and analyzed in 5 compartments (patella, medial, and lateral femur and tibia). The ankle brachial index (ABI) was obtained in all subjects. Linear regression analyses were used to assess associations of T2DM and UTE T2* relaxation times and the associations of ABI measurements and UTE measurements. Compared with nondiabetic controls, T2DM subjects had significantly lower mean T2*-UTE in the patella (mean difference 4.87 ms; 95% confidence interval [CI] 1.09-8.65; P = 0.015), the lateral tibia (mean difference 2.26 ms; 95% CI 0.06-4.45; P = 0.045), and the lateral femur (mean difference 4.96 ms; 95% CI 0.19-9.73; P = 0.043). Independent of diabetic status, subjects with higher ABI values, indicating better vascular health, had higher T2*-UTE of the patella (coefficient 15.2; 95% CI 3.3-21.4; P = 0.017), the medial tibia (coefficient 9.8; 95% CI 1.0-18.6; P = 0.031), and the lateral femur (coefficient 18.8; 95% CI 3.3-34.3; P = 0.021). T2*-UTE measurements of the deep cartilage layer were consistently lower in subjects with T2DM and in subjects with impaired vascular health, likely indicating increased mineralization of this layer.

Baseline structural tissue pathology is not strongly associated with longitudinal change in transverse relaxation time (T2) in knees without osteoarthritis

PurposeTo evaluate whether baseline MRI-defined structural abnormalities are associated with subsequent change in laminar femorotibial cartilage transverse relaxation time (T2) of participants without radiographic signs, symptoms or risk factors for knee osteoarthritis (OA). MethodWe studied all right knees with longitudinal MRI data of the refined Osteoarthritis Initiative Healthy Reference cohort. Baseline osteophytes, effusion-synovitis, Hoffa-synovitis, bone marrow lesions, cartilage lesions, and meniscus morphology and - extrusion were scored semiquantitatively from MR images by an expert reader. Deep and superficial layer cartilage T2 was computed in the medial and lateral femorotibial compartment (MFTC/LFTC) at baseline and at 1- and 4-year follow-up from multi-echo spin-echo MR images. Statistical analyses were performed using UNIANOVA. Results82 participants (age 54.1 ± 7.2y, BMI 24.2 ± 3.0 kg/m²; 61% women, bilateral Kellgren-Lawrence 0) were studied. Number of baseline MRI pathologies was not significantly associated with longitudinal change in MFTC or LFTC cartilage T2 over 1 or 4 years. Feature-specific analyses suggested that presence of baseline MFTC osteophytes may be associated with prolongation in superficial MFTC cartilage T2 over one (0.8 vs. 0.0 ms, p = 0.02) and four years (2.3 vs. 0.9 ms, p = 0.01), and that MFTC meniscal damage or extrusion may be associated with prolongation in deep layer T2 times over the first year (0.7 vs. 2.1 ms, p = 0.02). ConclusionsOur study does not provide evidence that, in knees without radiographic OA, baseline structural MRI abnormalities are strongly related to compositional progression during normal aging and/or the potentially earliest phases of the disease as measured by cartilage T2.

Radiographically normal knees with contralateral joint space narrowing display greater change in cartilage transverse relaxation time than those with normal contralateral knees: a model of early OA? – data from the Osteoarthritis Initiative (OAI)

To develop a model of early osteoarthritis, by examining whether radiographically normal knees with contralateral joint space narrowing (JSN), but without contralateral trauma history, display greater longitudinal cartilage composition change (transverse relaxation time; T2) than subjects with bilaterally normal knees. 120 radiographically normal knees (Kellgren Lawrence grade [KLG] 0) from the Osteoarthritis Initiative were studied. 60 case knees displayed definite contralateral radiographic knee osteoarthritis (KLG≥2) whereas 60 reference subjects were bilaterally KLG0, and were matched 1:1 to cases based on age, sex, and BMI. All had multi-echo spin-echo MRI acquired at year (Y) 1 and 4 follow-up, with cartilage T2 being determined in superficial and deep cartilage layers across 16 femorotibial subregions. T2 across all regions was considered the primary analytic focus. Of 60 KLG0 case knees (30 female, age: 65.0±8.8y, BMI: 27.6±4.4kg/m2), 21/22/13/4 displayed contralateral JSN 0/1/2/3, respectively. The longitudinal increase in the deep layer cartilage T2 between Y1 and Y4 was significantly greater (P=0.03; Cohen's D 0.50) in the 39 KLG0 case knees with contralateral JSN (1.2ms; 95% confidence interval [CI] [0.4, 2.0]) than in matched KLG0 reference knees (0.1ms; 95% CI [-0.5, 0.7]). No significant differences were identified in superficial T2 change. T2 at Y1 was significantly greater in case than in reference knees, particularly in the superficial layer of the medial compartment. Radiographically normal knees with contralateral, non-traumatic JSN represent an applicable model of early osteoarthritis, with deep layer cartilage composition (T2) changing more rapidly than in bilaterally normal knees. CLINICALTRIALS. NCT00080171.

Impact of contralateral radiographic status on longitudinal change of cartilage transverse relaxation time (T2) in radiographically normal knees, a model of early OA? – data from the osteoarthritis initiative

Purpose: Evaluating treatment for modifying structural progression at an early stage of OA requires models that display subtle synovial tissue alterations that occur early in the disease process, but still have a reasonable likelihood of progression. We have previously shown that radiographically normal (KLG0) knees with definite contralateral (CL) radiographic OA had a greater likelihood of incident ROA, and that KLG0 knees with CL radiographic joint space narrowing (JSN) displayed greater cartilage loss than those with radiographically normal CL knees. The purpose of this study was to use this model of “early” OA of a KLG0 case knee in a person with CL (non-posttraumatic) ROA, to determine whether baseline values and longitudinal change in cartilage composition differ compared with those with radiographically normal CL knees (controls). Methods: The data were obtained from the Osteoarthritis Initiative (OAI). 150 KLG0 case knees displayed CL ROA (KLG2-4; central readings vs.0.7), without reporting previous injury to that knee. Of those, 63 (50.8% female, age: 64.2±8.8 y, BMI: 27.6±4.4 kg/m2) were right knees with multi-echo spin-echo (MESE) MRIs (Fig.1) to support analysis of the cartilage transverse relaxation time (T2), a method previously shown to be related to cartilage composition and mechanical properties. 23 were CL KLG2 without JSN, 22 KLG2 with JSN grade1, 13 KLG3, and 5 KLG 4. The 63 case knees were matched 1:1 with 63 KLG0 controls of persons who were bilaterally KLG0 and had the same sex, similar age (64.3±8.7 y), and BMI (27.3±4.0 kg/m2). The 3-year change in cartilage T2 (between year 1 and 4 [Y1/4] follow-up) was determined from sagittal MESE MRIs (Fig.), analyzing the superficial and deep 50% of the cartilage in each of 16 femorotibial joint (FTJ) subregions. The mean T2-values across the superficial and deep cartilage layers of the entire FTJ were the primary analytic focus. Exploratory measures included T2 of the medial and lateral femorotibial compartment (MFTC/LFTC) and location-independent T2 shortening and lengthening scores (i.e. the sum of all negative / positive femorotibial subregion T2 changes). Results: The baseline T2 (Y1) was significantly greater in the case than in control KLG0 knees, both in the superficial and deep FTJ cartilage layers (paired t-test: p=0.01; Cohen’s D=0.40; and p=0.04; Cohen’s D=0.34, respectively). In the superficial layer, the effect tended to be stronger in the medial than in the lateral, and in the deep layer stronger in the lateral than in the medial compartment (Table 1).Table 1Cartilage T2 at the beginning of the observation intervalCase KLG0 kneesControl KLG0 kneesDifferenceSuperficial LayerMeanSD95% CIMeanSD95% CIPCohen DFTJ48.73.447.849.547.42.846.748.10.010.40MFTC49.24.248.150.347.73.746.848.60.020.37LFTC48.13.747.249.147.13.046.347.90.050.31Deep LayerFTJ37.72.337.238.337.02.036.537.50.040.34MFTC38.22.637.538.937.82.537.238.40.320.16LFTC37.32.636.637.936.22.235.736.80.010.44 Open table in a new tab When restricting analysis to those with CL JSN, the effect size (Cohen’s D) was 0.49 in the superficial and to 0.36 in the deep layer (data not shown). The longitudinal increase in medial and lateral T2 from Y1 to Y4 of the case knees was significantly different from zero; it also tended to be greater in case than in control KLG0 knees, but the case-control differences did not reach statistical significance (data not shown). Only when restricting the analysis to those with CL JSN, we observed a significantly (p<0.05) greater increase in deep layer T2 in the case than in the control knees in the FTJ, and also in the lateral compartment and location-independent lengthening score (Cohen’s D 0.45-0.46). No significant differences were observed in the longitudinal changes of the superficial layer (Table 2).Table 2Longitudinal change in T2 over 3 years of observationKLG0 with CL JSNKLG0 with CL KLG0DifferenceSuperficial LayerMeanSD95% CIMeanSD95% CIPCohen DFTJ1.01.90.41.60.91.50.41.40.850.04MFTC1.42.50.62.21.42.20.72.10.950.01LFTC0.62.2-0.21.30.41.9-0.21.00.820.06Decrease-15.316.1-20.4-10.1-15.110.2-18.4-11.80.96-0.01Increase31.717.726.037.429.717.824.035.40.610.11Deep LayerFTJ1.12.50.31.90.11.7-0.40.70.040.46MFTC1.33.30.22.40.32.4-0.41.10.140.34LFTC0.92.50.11.7-0.11.8-0.60.50.040.45Decrease-13.413.5-17.7-9.0-18.217.0-23.7-12.80.150.32Increase32.329.522.941.721.812.717.725.80.050.46 Open table in a new tab The increase in deep layer T2 was significantly correlated with location-independent measures of cartilage thickness loss in the FT joint (r=-0.27, p<0.01). Conclusions: This is the first study to explore whether cartilage T2 is sensitive to identifying compositional changes in cartilage in a model of “early” knee OA, i.e. a KLG0 knee with a CL non-posttraumatic ROA knee. Significant differences in superficial and deep layer cartilage T2 were observed at the beginning of the longitudinal observation interval. Similar to previous observations for the change in location-independent measures of cartilage thickness, significant longitudinal differences in T2 lengthening between case and control knees were observed in knees with CL JSN. These differences were limited to the deep layer, and were most prominent in the lateral femorotibial compartment. KLG0 knees with CL JSN hence may represent a model of early OA in which structure modification can be studied at an early disease stage.

Investigating the association of serum lipid biomarkers with biochemical cartilage composition using quantitative MRI – a pilot study

Purpose: There has been considerable interest in the association between osteoarthritis (OA) and metabolic syndrome (MS), whose components include abdominal obesity, diabetes, hypertension and dyslipidemia. OA is increasingly understood as a metabolic disease and recent epidemiologic studies suggest that OA pathogenesis could be linked to altered lipid metabolism. While there is evidence suggesting that the MS-associated OA phenotype is biochemically and structurally distinct from standard OA, the few studies that explored the relationship between serum lipid profile and OA utilized radiographic measurements which are insensitive for early and mild OA. Magnetic resonance imaging (MRI)-based T2 and T1ρ mapping are techniques that measure early degenerative changes of the whole cartilage layer while ultrashort (UTE) T2* mapping focuses on early degenerative changes of the deep calcified cartilage layer. Therefore, the goal of this study was to investigate the association of serum lipid levels with knee cartilage composition, assessed using T2, T1ρ and UTE T2* mapping. Methods: Fourteen study participants were recruited using the following inclusion criteria: 40-70 years of age, Kellgren Lawrence grade (KLG) 0-2 in at least one knee, no previous diagnosis of an inflammatory arthropathy, no knee pain most days of the month, no history of knee injury or knee surgery and no metal implants. Serum lipid biomarkers included total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), non-HDL cholesterol (sum of vLDL and LDL) and triglycerides. All subjects underwent bilateral standing anterior-posterior knee radiographs and 3 Tesla MRI imaging of the knee with the lower KL score using 3D multiecho T2, T1ρ and UTE sequences. Cartilage was segmented semi-automatically into five regions (patella, medial/lateral femur, medial/lateral tibia) for T2*UTE maps and six regions (patella, medial/lateral femur, medial/lateral tibia, trochlea) for T2 and T1ρ maps. T2, T1ρ and T2*UTE maps were computed after segmentation. Global values were calculated as the mean of all knee regions. Partial correlations and linear regression analyses were performed using standardized serum lipid biomarkers as predictors and global T2, T1ρ and UTE as outcomes adjusting for BMI. Results: The mean age of all subjects was 54.4 years (SD ± 4.0) with a higher proportion of males (71.4%), mean body mass index (BMI) was 29.4 (SD ± 2.8) and mean total WOMAC was 1.4 (SD ± 2.5). For serum lipid levels, the mean total cholesterol was 159.9 (SD ± 43.0) mg/dl, mean HDL was 44.8 (SD ± 11.0) mg/dl, mean LDL was 94.2 (SD ± 35.8) mg/dl, mean non-HDL cholesterol was 115.1 (SD ± 40.6) mg/dl and mean triglycerides was 104.7 (SD ± 69.0) mg/dl. As shown in Table 1, higher total cholesterol was significantly associated with higher global higher global UTE T2* (0.82 ms [0.07,1.57], r = 0.59, P = 0.035), higher LDL was significantly associated with higher global UTE T2* (0.80 ms [0.06,1.54], r = 0.58, P = 0.037) and higher non-HDL cholesterol was significantly associated with higher global UTE T2* (0.95 ms [0.27,1.63], r = 0.68, P = 0.011). No significant associations were found between serum lipid levels and global T2 and T1ρ. Conclusions: This cross-sectional study demonstrates that higher total cholesterol, LDL and non-HDL cholesterol were associated with higher UTE T2*, suggesting increased degeneration of the deep calcified cartilage layer. This layer may, therefore, have an important role in dyslipidemia-associated early cartilage degeneration. Potential pathophysiological mechanisms underlying these relationships include oxidized LDL’s role in cartilage destruction and ectopic bone formation, subchondral ischemia secondary to lipid deposits in cartilage and disrupted lipid metabolism leading to upregulation of pro-inflammatory signaling within cartilage and chondrocytes. Mechanisms through which dyslipidemia could contribute to OA development must still be fully elucidated. This study was supported by the National Center for Advancing Translational Sciences, NIH, through UCSF-CTSI Grant Number TL1 TR001871. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.Tabled 1Association of serum lipid biomarkers with cartilage UTE T2*. P-values < 0.05 are in bold.Coefficient[95% Conf. Interval]CorrelationP-valueGlobal UTE T2*Total cholesterol0.82[0.07,1.57]0.590.035HDL-0.29[-1.17,0.60]-0.210.491LDL0.80[0.06,1.54]0.580.037Non-HDL cholesterol0.95[0.27,1.63]0.680.011Triglycerides0.68[-0.15,1.51]0.480.101 Open table in a new tab

An efficient alternative to magnetic resonance (MR) composite relaxation (R2-R1ρ) mapping in human knee cartilage study at 3T

An efficient alternative to magnetic resonance (MR) composite relaxation (R2-R1ρ) mapping in human knee cartilage study at 3T

In vitro formed deep zone cartilage tissues: a model to study formation of the zone of calcified cartilage

In vitro formed deep zone cartilage tissues: a model to study formation of the zone of calcified cartilage

Patients with type 2 diabetes exhibit a more calcified deep cartilage layer compared to nondiabetic controls: a pilot study

Patients with type 2 diabetes exhibit a more calcified deep cartilage layer compared to nondiabetic controls: a pilot study

Femoral tunnel placement in single-bundle, remnant-preserving anterior cruciate ligament reconstruction using a posterior trans-septal portal

BackgroundAnatomic tunnel formation and remnant preservation are valuable aspects of anterior cruciate ligament (ACL) reconstruction. However, anatomic landmarks are difficult to observe during remnant-preserving ACL reconstruction (ACLR). The aims of this study were to evaluate the: 1) femoral tunnel location created with guidance from the apex of the deep cartilage margin (ADC) and footprint compared to anatomical reference; and 2) relationship between femoral tunnel location and outcomes of ACLR. MethodsA total of 109 ACLR patients without revision ACLR, multi-ligament reconstruction, peri-knee fracture, and osteotomy were included. The femoral tunnel was formed at the most proximal corner of the femoral footprint using a posterior trans-septal portal as the viewing portal. The distance from the tunnel center to ADC was measured by computed tomography and arthroscopy. The two measurements were then compared. Finally, femoral tunnel location was compared to the anatomic reference and correlated with the outcomes. ResultsThe average distance from ADC to the femoral tunnel center was 7.0 ± 1.4 mm as measured by arthroscopy, and 7.2 ± 2.0 mm using three-dimensional computed tomography. There was no statistically significant difference between the two methods (P = 0.420). Clinical and stability outcomes were significantly improved postoperatively. Clinical outcome was not related to femoral tunnel location; however, stability outcome was related to femoral tunnel location: the more proximally located femoral tunnels showed better stability. ConclusionThe ADC can be a possible landmark in remnant-preserving ACLR using a trans-septal portal. A more proximal femoral tunnel, which is located at the proximal corner of the ACL remnant, can provide stability advantage during remnant-preserving ACLR.

Regenerative Medicine: A Review of the Evolution of Autologous Chondrocyte Implantation (ACI) Therapy.

Articular cartilage is composed of chondrons within a territorial matrix surrounded by a highly organized extracellular matrix comprising collagen II fibrils, proteoglycans, glycosaminoglycans, and non-collagenous proteins. Damaged articular cartilage has a limited potential for healing and untreated defects often progress to osteoarthritis. High hopes have been pinned on regenerative medicine strategies to meet the challenge of preventing progress to late osteoarthritis. One such strategy, autologous chondrocyte implantation (ACI), was first reported in 1994 as a treatment for deep focal articular cartilage defects. ACI has since evolved to become a worldwide well-established surgical technique. For ACI, chondrocytes are harvested from the lesser weight bearing edge of the joint by arthroscopy, their numbers expanded in monolayer culture for at least four weeks, and then re-implanted in the damaged region under a natural or synthetic membrane via an open joint procedure. We consider the evolution of ACI to become an established cell therapy, its current limitations, and on-going strategies to improve its efficacy. The most promising developments involving cells and natural or synthetic biomaterials will be highlighted.

3414 Association of blood pressure and biochemical knee cartilage composition assessed by T2 relaxation time measurements: Data from the Osteoarthritis Initiative

OBJECTIVES/SPECIFIC AIMS: The goal of this study was to investigate the associations of systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) with knee articular cartilage composition using magnetic resonance imaging (MRI)-based T2 relaxation time measurements in study participants from the Osteoarthritis Initiative (OAI). METHODS/STUDY POPULATION: In this longitudinal study, 1,139 participants from the OAI, a multi-center, observational study of the evolution of knee OA, were selected using the following inclusion criteria: right knee Kellgren Lawrence (KL) score (radiographic classification of OA severity) 0-2 indicating no to mild radiographic OA at baseline, no history of rheumatoid arthritis at baseline, available blood pressure measurements at baseline, available T2 measurements in at least three knee compartments at baseline and 48-month follow-up. Linear regression models were performed using standardized values for SBP, DBP and PP as primary predictors and change in cartilage T2 over 48 months, a measure of cartilage matrix quality and degeneration, as the primary outcome. PP was defined as SBP minus DBP. Change in superficial layer and deep layer cartilage T2, which reflect differences in the laminar organization of knee cartilage T2, were also included as outcomes. Statistical models were adjusted for common risk factors for knee OA (baseline age, sex, BMI, KL score) as well as number of currently used anti-hypertensive medications (AHM) reported at baseline. We included AHMs whose primary indication was the treatment of hypertension including beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), thiazides, chlorthalidone, dihydropyridine calcium channel blockers (CCB) and aliskiren. All predictors, outcomes and covariates (except sex) were analyzed as continuous variables. We included interaction terms in the models to evaluate whether the covariates (age, sex, BMI, KL score, number of AHMs) modified the association of SBP, DBP and PP with cartilage T2. RESULTS/ANTICIPATED RESULTS: The average age of all study participants was 58.8 years (SD ± 8.6) with a higher proportion of men (59.4%), average body mass index (BMI) was 28.3 (SD ± 4.5), average SBP was 122.4 (SD ± 15.4) mmHg, average DBP was 75.5 (SD ± 9.6) mmHg and 469 (38.1%) study participants were taking at least one AHM. Higher baseline DBP was significantly associated with a faster increase in global T2 (0.22 [0.10,0.35], P &lt; 0.001), global deep layer T2 (0.20 [0.03,0.36], P &lt; 0.022) and global superficial layer T2 (0.39 [0.20,0.58], P &lt; 0.001). These associations were significant in both unadjusted and the models adjusted for age, sex, BMI and KL score. No significant associations were found between SBP or PP and cartilage T2 and no significant interactions were found between SBP, DBP, PP and the covariates. DISCUSSION/SIGNIFICANCE OF IMPACT: Higher baseline DBP was associated with a faster increase in knee cartilage T2, suggesting accelerated cartilage degeneration. This association was stronger for the superficial layer of knee cartilage T2 compared to the deep layer. Although further basic mechanistic studies are needed to elucidate the underlying pathophysiology of this relationship, these results suggest lowering DBP may influence knee OA.

Weight loss regimen in obese and overweight individuals is associated with reduced cartilage degeneration: 96-month data from the Osteoarthritis Initiative

To investigate change in knee cartilage composition over 96 months in overweight and obese participants with constant weight compared to those with weight loss (WL), and to assess how different WL regimens are associated with these changes. We studied right knees of 760 participants (age 62.6±9.0y; 465 females) with a baseline body mass index (BMI) >25 kg/m2 from the Osteoarthritis Initiative with mild to moderate or with risk factors for knee osteoarthritis. Participants losing weight (>5% of baseline BMI over 72 months; N=380) were compared to controls with stable weight (SW, N=380). Participants losing weight were categorized based on WL method (diet and exercise, diet only, exercise only) and compared to those with stable weight. Magnetic resonance imaging (MRI) at 3T was performed at baseline, 48- and 96-months. The association of WL and WL method with change in cartilage composition, measured with T2 mapping, was analyzed using mixed random effects models. Compared to SW, WL was associated with a significantly slower increase in global (averaged over all compartments) cartilage T2 (adjusted mean difference of change in T2 ms/year [95% CI] between the groups: 0.24 [0.20, 0.41] ms/year; P<0.001) and global deep layer cartilage T2 0.35 [0.20, 0.42] ms/year; P<0.001), suggesting slower cartilage deterioration. Compared to the SW group, slower increases in global T2 were observed in the diet and diet and exercise groups, but not in the exercise only group (P=0.042, P=0.003 and P=0.85, respectively). Our results suggest that WL may slow knee cartilage degeneration over 96 months, and that these potential benefits may differ by method of WL.

A unique anisotropic R2 of collagen degeneration (ARCADE) mapping as an efficient alternative to composite relaxation metric (R2 -R1ρ ) in human knee cartilage study.

Anisotropic transverse R2 (1/T2 ) relaxation of water proton is sensitive to cartilage degenerative changes. The purpose is to develop an efficient method to extract this relaxation metric in clinical studies. Anisotropic R2 can be measured inefficiently by standard R2 mapping after removing an isotropic contribution obtained from R1ρ mapping. In the proposed method, named as a unique anisotropic R2 of collagen degeneration (ARCADE) mapping, an assumed uniform isotropic R2 was estimated at magic angle locations in the deep cartilage, and an anisotropic R2 was thus isolated in a single T2W sagittal image. Five human knees from 4 volunteers were studied with standard R2 and R1ρ mappings at 3T, and anisotropic R2 derived from ARCADE on the T2W (TE = 48.8 ms) image from R2 mapping was compared with the composite relaxation (R2 - R1ρ ) using statistical analysis including Student's t-test and Pearson's correlation coefficient. Anisotropic R2 (1/s) from ARCADE was highly positively correlated with but not significantly different from standard R2 - R1ρ (1/s) in the segmented deep (r = 0.83 ± 0.06; 8.3 ± 2.9 vs. 7.3 ± 1.9, P = .50) and the superficial (r = 0.82 ± 0.05; 3.5 ± 2.4 vs. 4.5 ± 1.6, P = .39) zones. However, after eliminating systematic errors by the normalization in terms of zonal contrast, anisotropic R2 was significantly higher (60.2 ± 18.5% vs. 38.4 ± 16.6%, P < .01) than R2 - R1ρ as predicted. The proposed anisotropic R2 mapping could be an efficient alternative to the conventional approach, holding great promise in providing both high-resolution morphological and more sensitive transverse relaxation imaging from a single T2W scan in a clinical setting.

3D grating-based X-ray phase-contrast computed tomography for high-resolution quantitative assessment of cartilage: An experimental feasibility study with 3T MRI, 7T MRI and biomechanical correlation.

ObjectiveAim of this study was, to demonstrate the feasibility of high-resolution grating-based X-ray phase-contrast computed tomography (PCCT) for quantitative assessment of cartilage.Materials and methodsIn an experimental setup, 12 osteochondral samples were harvested from n = 6 bovine knees (n = 2 each). From each knee, one cartilage sample was degraded using 2.5% Trypsin. In addition to PCCT and biomechanical cartilage stiffness measurements, 3T and 7T MRI was performed including MSME SE T2 and ME GE T2* mapping sequences for relaxationtime measurements. Paired t-tests and receiver operating characteristics (ROC) curves were used for statistical analyses.ResultsPCCT provided high-resolution images for improved morphological cartilage evaluation as compared to 3T and 7T MRI. Quantitative analyses revealed significant differences between the superficial and the deep cartilage layer for T2 mapping as well as for PCCT (P<0.05). No significant difference was detected for PCCT between healthy and degraded samples (P>0.05). MRI and stiffness measurements showed significant differences between healthy and degraded osteochondral samples. Accuracy in the prediction of cartilage degradation was excellent for MRI and biomechanical analyses.ConclusionIn conclusion, high-resolution grating-based X-ray PCCT cartilage imaging is feasible. In addition to MRI and biomechanical analyses it provides complementary, water content independent, information for improved morphological and quantitative characterization of articular cartilage ultrastructure.

MRI UTE-T2* shows high incidence of cartilage subsurface matrix changes 2 years after ACL reconstruction.

Alteration of deep cartilage matrix has been observed following anterior cruciate ligament (ACL) injury, evidenced by elevated MRI UTE-T2* values measured in small, 2-D cartilage regions of interest. This Level I diagnostic study seeks to more thoroughly evaluate deep cartilage matrix changes to medial tibiofemoral UTE-T2* maps 2 years after ACL reconstruction and examine the relative utilities of 3-D compared to 2-D assessments of cartilage UTE-T2* maps. Thirty-eight ACL-reconstructed and 20 uninjured subjects underwent MRI UTE-T2* mapping. "Small" single mid-sagittal 2-D and larger 3-D "tread mark" regions of interest were manually segmented and found to be correlated in medial cartilage (r > 0.58, p < 0.005). 3-D analyses of UTE-T2* maps showed differences to medial tibial cartilage between ACL-reconstructed and uninjured subjects (p = 0.007) that were not detected by smaller 2-D regions (p > 0.46). Quantitative comparisons show 14/38 (37%) ACL-reconstructed subjects have values >2 standard deviations higher than uninjured controls. Among a subset of ACL-reconstructed subjects with no morphologic MRI evidence of medial tibiofemoral cartilage or meniscal pathology (n = 12), elevated UTE-T2* values in "small" 2-D femoral (p = 0.011), but not larger 3-D tread mark regions of interest (p > 0.13), were observed. These data show the utility of 2-D UTE-T2* assessments of mid-sagittal weight-bearing regions of medial femoral cartilage for identifying subclinical deep cartilage matrix changes 2 years after ACLR. Clinical Significance: Mid-sagittal single slice 2-D UTE-T2* mapping may be an efficient means to assess medial femoral cartilage for subsurface matrix changes early after ACL reconstruction while 3-D assessments provide additional sensitivity to changes in the medial tibial plateau. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:370-377, 2019.

Death of chondrocytes in Kashin-Beck disease: Apoptosis, necrosis or necroptosis?

The purpose of this paper was to investigate chondrocyte distribution and death in the cartilage in Kashin-Beck disease (KBD). Apoptotic chondrocytes were detected by TUNEL assay. Ultrastructural changes were examined by transmission electron microscope (TEM). Biochemical markers associated with apoptosis (eg, caspase-3) and necroptosis (eg, RIP3) were investigated by immunohistochemistry. In KBD cartilage chondrocyte death was characterized by paler staining of the cells. Multiple chondral cell clusters surrounded the areas lacking cells in the deep zone. The per cent of TUNEL-positive and RIP3-positive chondrocytes were higher in the middle zones of KBD samples; however, there was some positive staining for TUNEL but negative staining for caspase-3. Immunohistochemistry failed to detect significant differences in caspase-3 levels in KBD children compared to controls, suggesting that beside apoptosis necroptosis dominates as a cell death mechanism in the middle zone of cartilage from KBD children. To clarify further the presence of chondrocyte necroptosis in KBD, we performed TUNEL, caspase-3 and RIP3 staining in a rat KBD model which is based upon T-2 toxin treatment under selenium-deficient conditions. Apoptosis and necroptosis co-existed in the middle zone in this rat KBD model. Ultrastructural analysis of chondrocyte from deep cartilage revealed abnormal cells with numerous morphological changes, such as plasma membrane breakdown, generalized swelling of the cytoplasm and loss of identifiable organelles. Chondrocyte death by necrosis in the deep zone of cartilages in KBD may be a result of exposure to T-2 toxin from bone marrow or bloodstream under selenium-deficient nutrition status in KBD endemic areas. Chondrocyte death plays a key role in either the initiation or the progression of KBD pathogenesis.