Healthy Knees: Today’sHealthy Knees: Today s Treatments and the Potential of

Regenerative Medicine

Be Well Lect re SeriesBe Well Lecture SeriesUMass Memorial Foundation

May 15, 2009

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David C. Ayers, M.D.The Arthur M Pappas Professor & ChairThe Arthur M. Pappas Professor & Chair

Dept. of Orthopedics & RehabilitationUniversity of Mass Medical SchoolUniversity of Mass. Medical School

Orthopedist-in-ChiefUMassMemorial Healthcare SystemUMassMemorial Healthcare System

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OutlineOutline• Introduction• Normal Knee Joint• Arthritic Knee Joint• Arthritic Knee Joint• Current Non-operative Treatment• Current Operative Treatment

R l f St C ll d R ti M di i• Role of Stem Cells and Regenerative Medicine • Question and Answer SessionQ

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Orthopedic Facts• Orthopedic disorders are the most common cause of

disability in the US today; resulting in 147 million lostdisability in the US today; resulting in 147 million lost days of work

• One in six Americans has an orthopedic impairment• One in six Americans has an orthopedic impairmentOsteoarthritis, Osteoporosis, Back and Neck Pain

$215 billi t t th US ll• $215 billion = cost to the US annually. • Cost of DRG 209 is single greatest Medicare annual

expense (Total Hip and Total Knee Replacement)• Up to 70% of patients presenting to PCP office have a p p p g

chief complaint that is musculoskeletal

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Arthritis Facts

• An estimated 45 million es ed 5 oadults in the US have a form of arthritis4

• By 2030, an estimated 67 million Americans will have doctor-diagnosed arthritis6

4,5MMWR 2006: 55(40)1089-1092(data source 2003-2005 NHIS)

6Hootman JM, Helmick CG, Projections of US prevalence of arthritis and associated activity lijmitations. Arthritis and Rheumatism 2005:54(4)226-229 (Data Source: 2003 NHIS)

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Knee ArthritisKnee Arthritis• Prevalence growing in

ll l ith th iparallel with the aging , overweight adult US

l tipopulation• 50% over age 65 have

diagnosis of arthritis• 60% of women; making

it the leading chronic condition among women

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TKR Surgery

• “cost effective, reliable f h itreatment for the pain

and disability of d d k h i iadvanced knee arthritis”

NIH Consensus Panel 2001

• >600,000 TKR in US each year

• Is the single largest expenditure of the federal Medicare budget

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Total Knee Replacementp

• Projected growth; more than 600% increaseProjected growth; more than 600% increase by the year 2030F l d b i f th l ti• Fueled by aging of the population

• Desire to remain physically active later in p y ylife

• 35% TJR patients under the age of 65 and• 35% TJR patients under the age of 65 and part of the work force

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Knee Surgery Most CommonKnee Surgery Most Common Surgery in USA

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The Normal JointThe Normal Joint

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The Synovial JointThe Synovial Joint• Bones provide the framework for the body that

is both Rigid and Segmental• Joints are the point of articulation between 2• Joints are the point of articulation between 2

or more bones• Joints allow near frictionless movement • And work in concert with the neuromuscular

aspects of MSK system that results in a wide range of purposeful movementwide range of purposeful movement

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Synovial Joint

• Molded ends of 2 bones shaped to permit i f b h hmotion of one bone upon the other

• Bones connected by sleeve of connectiveBones connected by sleeve of connective tissue; the joint capsuleJ i t l i f th t b• Joint capsule receives further support by ligaments; provide bone to bone stability

• And further support by tendons; attach muscle to bone; that provide dynamicmuscle to bone; that provide dynamic stability

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Synovial Joint

• Exposed ends of bone covered with h id harticular cartilage that provides smooth

glistening surface• Ease of motion further enhanced by thin

glistening lining; the synovial membraneglistening lining; the synovial membrane and synovial fluid

• Synovial fluid that provides lubrication to the joint and nourishment to the cartilagej g

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A i l C ilArticular Cartilage• Unique Connective

Tissue• Ideally suited to

serve as elasticserve as elastic shock absorber

• Wear resistant weight bearingweight bearing material

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Articular CartilageArticular Cartilage• Contains no blood vessels, no nerves and no

lymphatics• Nourished by synovial fluidNourished by synovial fluid• Is 1-4 mm thick• Contains relatively few cells, chondrocytes,

dispersed in a connective tissue matrixdispersed in a connective tissue matrix• Chondrocytes are metabolically active but

h li i d bili li b ihave limited ability to replicate; obvious implications with regard to injury

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Articular CartilageArticular Cartilage• Chondrocytes y

arranged in layerslayers

• Connective i diff itissue differs in

orientation from superficial zones to deepzones to deep zones

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Articular Cartilage

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A i l C ilArticular Cartilage

• Metabolically Active• Constantly

synthesizing collagensynthesizing collagen and macromolecular proteogl cansproteoglycans

• Type II Collagenyp g

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Articular Cartilage; PG ContentArticular Cartilage; PG Content

C il i d b• Cartilage stained by toluidine blue• Intense metachromasia around etac o as a a ou dthe chondrocytes in the deep layerdeep layer• Represents staining of the proteoglycan

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ProteoglycanProteoglycan

• Linear protein backbone; hyaluronic acid• Polysac side chains attached to HA at rightPolysac. side chains attached to HA at right

angles; called glycosaminoglycans3 di i f GAG• 3 distinct components of GAG

Chondroitin 6-sulfateC o d o t 6 su ateChondroitin 4-sulfateKeratin sulfate

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ProteoglycansProteoglycans

H20H20H20H20H20

H20H20H20H20

H20

H20

H20H20H20

Keratan Sulphate

H20H20H20

H20

Keratan SulphateChondroitin Sulphate

H l i A idAggrecan

Glycosaminoglycans

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Hyaluronic Acid

E th b t di hi t h i t d h

New Tools and Imaging Techniques Needed in Patient Centered ResearchEven the best radiographic techniques are not good enough:

fluoroscopically assisted semiflexed PA radiographs

Good Alignment: reproducible but p

insensitive to early OA

Poor Alignment: false joint space

narrowing

22Ann Rheum Dis. 2008 Feb 7

delayed Gadolinium-enhanced MRI of Cartilage (dGEMRIC)

Basic Principle:Unequal distribution of charged cartilage structural molecules

predicts a broad range of detection in normal vs. OA cartilage

Histologic Evaluation (ex vivo): Charged dye (blue) detects healthy cartilage; lack of dye (white) detects

cartilage degradation

dGEMRIC Evaluation (in vivo): Charged contrasts detect healthyCharged contrasts detect healthy cartilage (yellow) and focal (red)

loss of cartilage

23J Orthop Res. 2008; 26(3):281-91.

Clinical use of delayed Gadolinium-enhanced MRI of Cartilage (dGEMRIC):

Femoropatellar Joint: Tibiofemoral Joint:Femoropatellar Joint: Tibiofemoral Joint:

Normal:

Early OA:

24Magn Reson Med. 2001; 45(1):36-41.

H-12692UMass Medical School Department of Orthopedics

IRB d H S bj t T i lIRB-approved Human Subjects Trial:

‘Efficacy of a disease-modifying osteoarthritis drug using dGEMRICi ith t th iti i d i din women with osteoarthritis in a a randomized,

placebo-controlled, double-blind trial’ Goals:

Longitudinal study in a small female OA patient cohort (n=40) to:

•Map unilateral knee OA cartilage lesions (ROIs) at baseline (MRI)

•Randomize 20/40 OA subjects to potential DMOAD (FDA-approved) group

R d i 20/40 OA bj t t l b t l•Randomize 20/40 OA subjects to placebo control group

•Observe changes in GAG concentrations over time (2 & 4 months) in both control and treatment groupsin both control and treatment groups

•Calculate & report effects for larger-scale trial(s)/funding

25Fanning PJ, Ayers DC (2008)

Step 1: Remember the AnatomyBONES

FEMURFEMURPATELLA

TIBIAFIBULA

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ANATOMY: CartilageN O : Ca ageCARTILAGE ARTICULAR

CARTILAGECARTILAGE

MEDIAL

LATERALMENISCUS

MENISCUS

ARTICULAR

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CARTILAGE

Arthroscopic Knee SurgeryArthroscopic Knee Surgery• Out-Patient• Small portals

C i f• Correction of meniscus tears, loose bodiesbodies

• Does not hchange

arthritis

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MENISCAL TEARS:MENISCAL TEARS: • Characteristics of the Pain

– PAIN USUALLY LOCATED OVER SIDE OR BACK OF KNEE

– PAIN WORSE WITH MOVEMENT, BETTER AT REST

• LOCKING KNEE GETS STUCK IN ONE POSITION or• LOCKING - KNEE GETS STUCK IN ONE POSITION or unable to fully extend knee

• Age Specific features:g p– IN PEOPLE < 40 yo SUDDEN ONSET &

ASSOCIATED WITH TWISTING INJURY– PEOPLE > 50 yo MAY NOT HAVE INJURY

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MENISCAL TEAR

ARTHROSCOPIC VIEWMENISCUS

Normal MeniscusMENISCAL TEAR

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Treatment of Degenerative MENISCAL TEARSMENISCAL TEARS

TEARTEAR

TORN SEGMENTREMOVED

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REMOVED

MENISCAL REPAIR IN YOUNGand Rim Tears

MENISCUSTEAR

SUTURESSUTURES

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Treatment of ArthritisTreatment of Arthritis• Conservative options; first line of treatmentConservative options; first line of treatment

– Physical therapy for ROM and strengtheningW i ht R d ti– Weight Reduction

– Glucosamine and Chondroitin Sulfate– Tylenol and anti-inflammatory drugs– Steroid (cortisone) injectionSteroid (cortisone) injection– Synvisc injections

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UnicompartmentalUnicompartmental Knee ReplacementKnee Replacement

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Compartments of The KneeCompartments of The Knee

Medial: Lateral : NORMALMedial: NARROWEDSPACE

SPACE

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TJR OUTCOME STUDIES SHOW:

• Successful Surgical P d

TKRProcedure

• Sustained Pain Reliefnt of choice tating

• Improved Physical F nction

ood/excellent Function

• Best QUALY Analysis for ollow-up

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yANY surgical procedure

UMASS Excellence in TKRUMASS Excellence in TKR• Gender TKR; ;

made specifically for womenfor women

• High Flexion TKR

• Ranawat AwardRanawat Award from the Knee SocietySociety

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Younger PatientsYounger Patients

• More reasonable to do joint replacement with current options availablep

• Often an option for patients in 50’sA i I fl A h i i• Any age in Inflammatory Arthritis

• Patients must limit their activities to maximize at e ts ust t t e act v t es to a ethe longevity of their implants

no high impact activities– no high impact activities

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Treatment of ArthritisTreatment of Arthritis

• Arthroscopy– Not indicated for Arthritis– Indicated for meniscal tear or mechanical symptoms

• Joint replacement surgeryp g y– Elective surgical procedure– Never an emergencyg y– Indication is PAIN RELIEF– One of the most successful operative treatments in all ofOne of the most successful operative treatments in all of

medicine today; a Miracle of Modern Medicine

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Cartilage Repair and RegenerationCartilage Repair and Regeneration

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OAT ProcedureOAT Procedure

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ARTICULAR CARTILAGE INJURY

CARTILAGEDEFECT

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AUTOLOGOUS CARTILAGE CELL TRANSPLANTATION

CARTILAGEDEFECT PATCH & CELLS

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The “New Patient”The New Patient• Younger

M A i• More Active• More Educated• More Informed• Heavier• Heavier• More #’s

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Thank You

F Y A iFor Your Attention

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Joint StabilityJoint Stability• Congruity of opposing bone surfaces• Support provided by fibrous capsule, ligaments

and in some cases menisciand in some cases menisci• Muscular contraction provides dynamic

stabilization of the joint, an important stabilizer

• Synovial fluid contributes some by inhibiting distraction of the bones acting as an adhesivedistraction of the bones, acting as an adhesive

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Minimally Invasive Joint Replacement:

• Definition- What is it?• Mini-incision vs. MIS• AdvantagesAdvantages• Disadvantages• Future

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ANATOMY: LigamentsN O : ga e sLIGAMENTS

MCL

LCLLCL

ACL PCLACL PCL

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ANATOMY; MusculotendinousN O ; uscu o e d ousTENDONS QUADRICEPS

MUSCLEMUSCLEQUADRICEPS

TENDONTENDON

PATELLATENDON

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Hi J iHinge JointKnee and ElbowKnee and Elbow

• Acts similar to• Acts similar to door hinge All fl i• Allows flexion and extension in 1 l1 plane

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GAGGAG

Have negative charged side chain

• Produces a spatial lattice structure • Lattice is hyper hydratedLattice is hyper hydrated • 80% water; water molecules assist in

k i th ti l h dkeeping the negatively charged groups in GAG apart

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Cartilage MatrixCartilage Matrix

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Cartilage under compressionCartilage under compression

• Under compressive force, some water is expelled from the matrixp

• Water returns into the cartilage with release of the compressive forcethe compressive force

• Allows cartilage to maximize elasticity and permit it to sustain cumulative trauma of life so effectivelyso effectively

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Cartilage MatrixCartilage Matrix

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OsteoarthritisOsteoarthritis

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The OptionsThe Options♦ Non-medical Therapy

O tiOptions• Pacing activities

J i i• Joint protection• Exercise/Physical

ti itactivity• Application of heat and

coldcold• Self-care skills

♦ M di ti♦ Medications♦ Therapy

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Arthritis Warning Signs:Arthritis Warning Signs:YOUR Signs to See Your Doctorg

♦Pain♦Stiff♦Stiffness♦Difficulty movingy g♦Swelling

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Th K SThree Key Steps

♦ A history (questions about

your symptoms)

♦ A physical examination

♦ X-rays and other tests

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Synovial MembraneSynovial Membrane• Derived from

mesenchymal cellsmesenchymal cells• Functionally comprised

f llof two cell types• Phagocytic cells; similar gocy c ce s; s

to macrophage, activated by degradation of matrixby degradation of matrix

• Secretory cells; secrete synovial fluid

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The Normal JointThe Normal Joint

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Orthopedic SurgeryBi l d Bi h iBiology and Biomechanics

Th k !Thank you!

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MENISCAL TEARSMENISCAL TEARS

• TWISTING INJURY CAUSES TEARING OF MENISCUSTEARING OF MENISCUS

• DEGENERATIVE TEARS ASSOCIATED WITH MILD ARTHRITIS not amenable to repairARTHRITIS not amenable to repair– OCCUR WITHOUT KNOWN TRAUMA

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