Articular cartilage: from Form to Function ISMRM 16th Scientific Meeting & Exhibition

Ontario, Canada

Hollis G. Potter, MD Chief, Magnetic Resonance Imaging

Director of Research, Dept. of Radiology & Imaging Hospital for Special Surgery

Professor of Radiology Weill Medical College of Cornell University

Peter A. Torzilli, PhD

Director, Laboratory for Soft Tissue Research Hospital for Special Surgery

Articular cartilage

Viscoelastic substance with strong imaging and biomechanical anisotropy Signal properties dependent on:

Cellular composition of collagen, proteoglycans and water MR pulse sequence utilized

– Moderate TE FSE more sensitive to partial thickness lesions – Fat suppressed 3D GRE with square voxels more amenable to automatic

segmentation and volume quantification methods Orientation of collagen in different laminae of cartilage

MRI of Articular Cartilage Imaging Options

Traditional MRI sequences ineffective 3-D fat suppressed spoiled gradient echo High resolution moderate TE fast spin echo Fat suppressed fast spin echo MR arthrography (direct vs indirect) Fluid sensitive GRE

– Driven equilibrium FT (DEFT) – Double echo steady state (DESS) – Refocused steady state free precession (SSFP)

Ultrashort TE imaging (Bydder) – Projection reconstruction spectroscopic imaging

Cartilage Segmentation: 3-D Surface

Volumetric analysis of articular cartilage

• Cartilage volume: function of both thickness and surface area - longitudinal changes affected by alteration in cartilage thickness (elevation or reduction) AND alterations in cartilage surface area (osteophyte formation)

• Cicuttini et al compared tibial cartilage volume and radiographs (JSN/osteophytes) in 252 pts., demonstrating a strong negative linear association between tibial cartilage volume and increasing grade of JSN (Arthritis Rheum 2003; 48:682-688)

• Raynauld et al studied 32 pts with symptomatic knee OA: no statistical correlation between loss of cartilage volume and subjective clinical outcome measures (Arthritis Rheum 2004; 50:476-487)

• Raynauld et al studied 107 pts. from a OA trial using bisphosphonate with volume at baseline, 12 and 24 months. Cartilage volume loss was statistically significant rel. to baseline (Arthritis Research & Therapy 2006; 8:1-12)

- predictors of fast progression were: • Meniscal extrusion • “Severe” medial meniscal tear • Bone marrow edema • High BMI and age

HSS Clinical Articular Cartilage Pulse Sequence

Long TR 3500-5000/ moderate TE 34msec − accentuates inherent MTC in FSE: Off-resonance RF pulse saturates the bound pool

of water p+ (normally have very short T2); results in ↓ SI from free water p+ after exchange of magnetization

Adequate FOV to cover anatomy, high matrix (512 x 256-416) imparts superior spatial resolution

Wider BW (minimize chemical shift, reduce IES) Thin slices with no gap

HSS Clinical Articular Cartilage Pulse Sequence JBJS 1998; 80A(9):1276-1286

Validated using arthroscopy as the standard (616 surfaces; 88 pts) 88 patients (ave. age 38 yrs) 3 arthroscopists; 2 independent MR readers Sensitivity 87%; specificity 94%; accuracy 92%

− weighted kappa = 0.93 MRI within one grade of arthroscopy in 97% (599/616)

MODIFIED ICRS© CARTILAGE CLASSIFICATION P A T H O L O G I C A L Change

A R T H R O S C O P I C Findings

M R I Findings

Superficial lesions : Extending down to < 50% of cartilage depth

Grade Fissures rillation / Fib

2 Involving < 50% of cartilage thickness

Linear to ovoid foci of increased signal Involving < 50% of cartilage thickness

Cartilage defects : Extending down to > 50% of cartilage depth down to subchondral bone

Grade Blisters sures / Fibrillation

/ Fis3

Involving > 50% of cartilage thickness

Linear to ovoid foci of increased signal Involving > 50% of cartilage thickness

Normal Articular Cartilage Grade 0 Normal cartilage with gray scale stratification

Superficial lesions : Chondral softening

Grade Softening to probe

1 Increased signal in articular cartilage

Penetration of subchondral bone Grade Expose chondral bone d sub

4 Complete loss of articular cartilage or surface flap with loss of subchondral plate

M R I Images

Cartilage Structure: Proteoglycans

Chondrocytes comprise <10% of cartilage volume Water most abundant component; majority contained within intersitial space created by

matrix Material properties attributed to extracellular matrix elements (collagen and PG) Compressive strength: proteoglycan monomers with neg. charged GAGs (CS or KS)

radiate from the protein core Monomers bind to HA to form aggregate that resist compression due to hydrophilic

structure Imaging: assess H+ bound to PG by electrostatic charge (assess fixed charge density)

Sodium MRI Gd-DTPA-2 techniques (dGEMRIC) T1 rho imaging

T1ρ : Assessment of proteoglycan content at 3T

Assess low frequency interactions between H+ in macromolecules and free water Spin-lattice relaxation in the rotating frame: uses cluster of RF pulses to “lock”

magnetization in the transverse plane, followed by a second RF to drive longitudinal recovery

T1 rho imaging: Previous studies

• T1 rho reflects proteoglycan content and correlates to fixed charge density in both trypsinized bovine and clinical osteoarthritis specimens at 4T

– Normalized T1 rho rate (1/T1ρ) was compared to assessment of FCD from Na23 and T1 rho was compared to histology (alcian blue-PAS)

– Percentage change of R1ρ and FCD was highly correlated (R2 >0.85; p<0.001) – T1 rho values increase as proteoglycan concentration decreases

• (Wheaton, Reddy et al. J MRI 2004;20:519-525) • T1 rho has been shown to be clinically feasible, scanning healthy and symptomatic

volunteers at 1.5T – Cartilage lesions were seen 25% better on T1rho sequences when compared with

T2-weighted sequences • (Reddy Regatte et al J MRI 2003;18:336-341; Duvvuri et al Radiology

2001;220:822-826) T1 rho imaging: Previous studies

• Wheaton et al. J Ortho Res 2005;23:102-108 • Porcine model injected with IL-1β (mediator of cartilage catabolism; up-regulates

MMPs) vs. saline – Scanned at 4T with single-slice T1 rho (compared in vivo and ex vivo data)

compared to FCD (Na23); histologic and immunohistochemical staining was also performed

– Strong correlation coefficient between in vivo and ex vivo data R2 = 0.86 (p<0.001)

– Proteoglycan loss was seen by histologic staining as well as decreased sodium concentration on Na23 MRI

• Li, Han...Majumdar et al. Magn Res Med 2004;51:503-509 • Spiral multislice T1 rho sequence tested on agarose phantoms, healthy volunteers and

patients with OA at 3T – T1 rho values elevated in OA patients compared to healthy controls; T2 values

not significantly different between OA patients and controls – T1 rho may be a more sensitive indicator of cartilage degeneration than T2 – Limitation: spiral acquisition which limits its utility to the axial plane of imaging

Cartilage Structure: Collagen

Type I collagen fibers provide tensile strength: long ratio of length to thickness Intramolecular and intermolecular cross-links provide structural rigidity to the

collagen fibrils and prevent slippage or sliding between the collagen molecules Nimni (1983)

Cartilage Structure: Collagen Deep radial zone (40-60%): collagen oriented perpendicular to subchondral zone—strong

angular dependence: vertical striations evident and short T2 values Transitional zone (20-30%): more random collagen orientation—less angular dependence

and longer T2s Superficial zone (<10%): parallel to surface (beyond resolution of clinical MRI) Imaging of collagen orientation and macrostructure

Structural anisotropy Quantitative T2 mapping: internuclear dephasing of unbalanced dipole

interactions: e –t/T2* Xia et al; Osteoarthritis and Cart 2001; 9:393-406

Bovine explants: Effect of enzyme degradation on T1 map / T1 rho Control Hyaluronidase

Treated

T2 Map

T1 Rho*

Whole Deep Superficia

46.8 ± 21.0 25.3 ± 3.5 56.5 ± 18.3

46.8 ± 20.6 32.1 ± 7.1 59.1 ± 24.4 (no )

79.1 ± 12.0 67.1 ± 8.0 74.3 ± 1.4

82.4 ± 26.3 63.4 ± 4.7 101.3 ± 21.1 ( )

Whole Deep Superficia

Collagenase Treated

52.7 ± 29.7 32.6 ± 3.3 74.7 ± 31.5 ( )

90.1 ± 39.8 67.5 ± 2.6 121.1 ± 54.1 ( )

T2 mapping at HSS

Developed modified multislice multiecho sequence that minimizes the quantitative error generated by stimulated echo formation (J MRI 2003; 17(3):358-364)

− Suitable for clinically relevant field strengths Validated T2 mapping at 1.5T in ovine meniscectomy model and bovine explants using

PLM and FTIR-S as standards (AJSM 2006; 34:1464-1477 ; ICRS 2004, 2006) Studied in tissue engineered rabbit cartilage (ICRS 2006) Currently we have studied over 300 patients following cartilage repair

Bovine Model of Osteoarthritis T2 mapping at 1.5T correlated to India ink preparations, Biomechanical testing,

Mankin scores and PLM (p<0.05; Spearman’s Rank Correlation) Kelly et al. AJSM 2006; 34:1464-1477

Angular Dependence of Cartilage: Structural Anisotropy

1/T2 = k(3cos2θ –1)

Imaging of Cartilage Structure and Function: Biomechanical testing ■ Stress-relaxation test in unconfined geometry ■ Static compression (Young’s modulus) followed by dynamic compression (mechanical

properties dependent on loading rate) ■ Proteoglycans (compressive strength)

■ Gd-DTPA-2 techniques (dGEMRIC) • Correlated to static (compressive) strength at 9.4T*

■ Collagen fibrils (tensile strength) ■ Quantitative T2 mapping ■ Correlated to dynamic mechanical properties at 1.5T & 9.4T* *Lammentausta et al; JOR 2006;24:366-374

■ Load response to focal indentation as index of stiffness ■ dGEMRIC index of tibial explants at 8.45T correlated to local stiffness when

GAG index was normalized to depth of indented tissue but not for the full thickness GAG index

Samosky, Burstein et al: JOR 2005; 23:93-101 ■ Dynamic MR elastography to obtain shear stiffness measurement at 1.5T (Lopez et al;

JMRI 2007; 25:310-320)

Unconfined Compression – Smooth Platens

Unconfined Compression – Smooth Platens

Solid, non-porous

Solid, non-porous

Solid, non-porous

Solid, non-porous

Chondrocytes in gel (collagen, agarose, HA …)

Biomechanical Response to Constant Strain

Relaxation: Apply constant strain, measure stress

Stress

Aggregate Modulus vs Histology Grade Armstrong & Mow (1982)

DeformedArticular Surface

High Fluid Pressure=> Fluid Imbibition

Joint Load

Joint Displacement

Interstitial Fluid

Mechanical Consolidation => Fluid Exudation

Static Load (Standing)Static Load (Standing)

Synovial Fluid Squeeze-Film Flow

Deformed Articular Surface

Contact Mechanical Consolidation

=> Fluid Exudation

Squeeze-Film Cut-Off Joint Load

Joint Displacement

SSttaattiicc LLooaadd ((SSttaannddiinngg))

Motion

Fluid exudation as cartilage is compressed

Hydrodynamic Fluid Flow

Shear Plowing

Joint Load

Fluid imbibition as cartilage is relaxing

SSlliiddiinngg MMoottiioonn ((WWaallkkiinngg))

Normal Histology Grade Score OA 0

0.2

0.4

0.6

0.8

1

1.2

0 1 2 3 4 5

Aggregate Modulus, Ha

(MPa)

Joint motion (i.e. load) is one of the primary mechanisms for the formation, maintenance, degradation and normal repair (?) of the articular cartilage in all diarthroidal (movable) joints. Uncovering the surface will enhance fluid imbibition and deformation recovery. Oscillating motion (cover/uncover) is essential for health and function. All joints are reciprocating (cover/uncover) Joint Inflammation Post Trauma Injury

Inflammation

Bon

Cartilage

Bon

Indenter5 mm

6.35 mm

0

Stress, MPa

25 40 50 60 70 80 90 MPa Cartilage

Bone

Bone bruise

σ, MPa

Cartilage failure Bone failure

Migration

Proliferation

Remodeling

Synovial membrane

Capsule

Bon

Synovial space

PMN MNL

Chondrocytes

Cartilage

Leukocytes: Polymorphonuclear (PMN) + Monocytes

Courtesy of Dejan Milentijevic, Ph.D.

Osteochondral Matrix Response to Severe Joint Trauma Milentijevic D, Aslani K, Potter HG, Torzilli PA Stress – Strain Response of Cartilage

Strain, mm/mm0.00 0.05 0.10 0.15 0.20 0.25 0.30

Stre

ss, M

Pa0

10

20

30

40

50

60

70

Stress = 60 MPaStress Rate = 400 MPa/sec

Surface failure

of cartilage Discussion

• The maximum compressive strain (~30%) did not change with high stress magnitudes (40-60 MPa) due to cartilage stiffening (hydrostatic pressure). (without breaking through the bone)

• Superficial cracks (~15% depth) occurred due to matrix failure in tension causing cell death (occurred only at fissures).

• There was no swelling (measured water content using wet and dry weight) even with the presence of superficial cracks, indicating that no significant matrix damage occurred.

• Acute phase of 7 days post impaction did not initiate cartilage degenerative processes (no change in PG or collagen loss).

• Subchondral bone compliance appears to have an important role in protecting the cartilage during joint trauma.

• Severity of trauma (stress magnitude) may not be a reliable predictor of post-traumatic arthritis in acute phase of trauma (no change in water, PG and collagen content).

Articular Cartilage Injury following Acute ACL Tear

Spindler et al (AJSM 1993; 21:551-557) evaluated 54 pts with ACL tear and ACLR – 46% (25/54) had articular lesion at arthroscopy (LFC>LTP>MFC>MTP)

Johnson et al (AJSM 1998; 26:409-414) evaluated 10 pts with acute ACL tear underwent biopsy of LFC during ACLR

– Chondrocyte degeneration, loss of PG, osteocyte necrosis and empty lacunae degeneration

• Tiderius et al (Arthritis and Rheumatism 2005; 52:120-127) evaluated cartilage glycosaminoglycan loss in the acute ACL injury with delayed post-gadolinium MRI

– 15 out of 24 patients (63%) had loss of GAG in both medial and lateral femorotibial surfaces

– Suggests generalized alteration in matrix within the knee cartilage following ACL injury

Cartilage Repair: Methods of Repair

Articular cartilage has little to no capacity to undergo spontaneous repair – avascular; unable to regenerate across a physical gap

Debridement Marrow stimulation (microfracture)

Osteochondral transfer – autologous (mosaicplasty; OATS) – allograft (fresh cadaveric tissue)

Tissue Engineered Cartilage (three requirements) – matrix scaffold

• carbohydrate based polymers (polylactic acid) • protein based polymers (collagen, fibrin)

– cells • chondrocytes • chondroprogenitor cell pools (cambial layer of periosteum and

perichondrium) • mesenchymal stem cells from the bone marrow or synovial membrane

– signaling molecules (growth factors or genes) Synthetic acellular techniques (scaffold)

– polylactide-co-glycolide copolymer and calcium sulfate (porous) Imaging as a Primary Outcome Measure Morphologic Analysis: Cartilage Repair

Signal intensity of tissue (ROI analysis) Integrity/hypertrophy of periosteal flap (ACI) Morphology; presence/absence of displacement (ACI/ OCA) Interface with native cartilage Volume of repair “fill” Appearance/morphology of subchondral bone Assess adjacent and opposite articular cartilage Presence/absence of inflammatory synovitis

CORR 2004;422: 214-223

Autologous cartilage transplantation (Peterson): autologous chondrocyte harvest, cloning in culture, followed by arthrotomy and

reimplantation with periosteal flap Miller and Cole, Op Tech in Orthop 2001; 11: 145-150.

Microfracture (picking): Steadman

Miller and Cole, Op Tech in Orthop 2001; 11: 145-150. Imaging of Microfracture

Prospective study of 48 patients treated with microfracture evaluated by validated clinical outcome instruments and cartilage sensitive MRI

− bony overgrowth was noted in 25% of patients, but did not have a negative effect on clinical outcome scores

− adverse functional scores after 24 months did correlate with poor percentage fill J Bone Joint Surg 2005; 87(9):1911-1920

Osteochondral autografts (mosaicplasty) Miller and Cole, Op Tech in Orthop 2001; 11: 145-150

Imaging of Osteochondral Allografts

Prospective, longitudinal study of cartilage defects treated with hypothermically stored fresh osteochondral allografts using validated clinical outcome instruments and cartilage sensitive MRI

Allografts remain intact without displacement − fissures noted at the graft/host interspace in 16/19 (84%) grafts − poor incorporation was noted in 6/19 (32%) grafts, three of which demonstrated

an intense bone marrow edema pattern and the remainder of which demonstrated frank subchondral marrow fibrosis (low signal on all pulse sequences)

− collapse of the subchondral bone in the graft has been noted to correlate with lack of bony integration based on signal characteristics

J Bone Joint Surg 2007; 89A(4):718-726

Quantitative MR Assessment of Articular Cartilage Biochemistry: Clinical Utility

Osteoarthritis: Breakdown of matrix − Swelling of PG, increase cartilage permeability − Disruption of collagen with increased mobility of water yielding prolongation of

T2 and loss of stratification ■ Assess “disease modifying” abilities of pharmaceutical therapy

(viscosupplementation) ■ Optimize timing of meniscal transplantation/realignment/osteotomy

Cartilage Repair − Assess components of matrix in repair tissue − Assess response of adjacent hyaline cartilage to surgical repair − Imaging to serve as a primary outcome variable for the FDA? − Obviate the need for second look arthroscopy/biopsy −

Imaging &Cartilage Repair Trials • Initial assessment of axial alignment (radiographs) • Preclinical outcome measures should parallel Phase I and Phase II clinical measures • Importance of OBJECTIVE outcome measures to assess biology

MRI of Articular Cartilage

Standardized, validated sequences available for all joints Sequences should not be limited by instrumentation Provide noninvasive detection of traumatic injuries Monitor progression of cartilage degeneration in OA and disease status in RA Provide objective outcome assessment for cartilage repair techniques Future development: detect early changes in matrix prior to morphologic alteration

− noninvasive tissue characterization of repair tissue − noninvasive assessment of materials properties − optimize timing of meniscal transplantation/PF realignment/osteotomy

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