Musculoskeletal Regenerative Medicine:

Platelet Rich Plasma

Orthopedic Regenerative Medicine and Joint Preservation Center of Santa Rosa

Raymond Severt, M.D. - Director1144 Sonoma Avenue, #121

Santa Rosa, CA 95405

(707) 978-4322RegenMedSR.com

What is Regenerative Medicine

Branch of medicine

replacing, engineering, or regenerating human cells, tissues or organs

to restore or establish normal function

What is Orthopedic Regenerative Medicine

Augment the natural healing process to heal or even “grow back” the damaged tissue

muscle

tendon

ligament

cartilage

What is PRP (Platelet Rich Plasma)?

Concentration of platelets in plasma

typically 5X - 10X concentrated (250K/microlitres = normal count)

With RBC/WBC - red

Without RBC/WBC - clear

How Do You Make PRP?Blood draw from patient

30 - 60 mlProcess in centrifuge to get the type of PRP you want

What are Platelets?

come from megakaryocytic

contain growth factors in alpha-granules

become activated and release factors

Platelet Activation Releases FactorsPlatelets release various growth factors when activatedGrowth factors have various effects

In Order to Fix Something -We need to know how it works.

Joints and Arthritis

What Happens in JointsBalance: Repair vs. BreakdownRepair/Maintanence

healthy chondrocytes

controlled matrix remodeling

normal stability/loads

normal cartilage/bone interfaces

normal lubrication

Breakdown

chondrocyte hypertrophy

matrix breakdown

excessive instability and loads

abnormal bone/cartilage lesions

poor lubrication

Arthritis What happens in an arthritic joint?

ArthritisCartilage wears out

chondrocytes unhealthy/poor quality matrix - breaksdown

Poor lubrication - hyaluronic acid/lubricin (SZP - Proteoglycan 4)

increased friction - wears out

Inflammation - pain

Arthritic Joint - The “BAD” Molecules

MMP’s - matrix metalloproteinases - collagenases, gelatinases, stromelysins - degrade collagen, proteoglycans, elastin, etc.

IL-1, TNF - interleukins - inflammatory - enhance MMP’s

ADAMTS - disintegrins - prevent platelet function

CATABOLIC - BREAKDOWN

What About “GOOD” Molecules?TGF - tissue growth factor

TIMP-1&2 - tissue inhibitor of metalloproteinases

IRAP - interleukin receptor antagonist protein

A2M - alpha 2 macroglobulin (useless by itself - so drug companies barking up the wrong tree)

Block the BAD molecules - ANTI-CATABOLIC (ANABOLIC)

PRP (Platelet Rich Plasma) Reduces “BAD” Molecules

Increases “GOOD” Molecules

What About “Traditional” Treatments?

Are there problems?

NSAIDS

Corticosteroids

Surgery

(Physical Therapy ALWAYS GOOD!)

NSAIDSCommonly taken

Multitude of side-effect

Very significant problems

ulcers, bleeding, heart attack, stroke, kidney and liver failure

Inhibit chondrocytes and stem cells

NSAIDS - Black Box Warning“Strongest warning that the FDA requires. Reserved for drugs that pose a significant risk of serious or life-threatening adverse effects, based on medical studies”

Cardiovascular Risk• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (See WARNINGS).• These drugs are contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (See WARNINGS).Some taken off market - Vioxx, Bextra

Corticosteroids Injections

Commonly performed

Temporarily reduce inflammation

Inhibit healing

Cause damage to cartilage and soft tissue structures

These Medications:Don’t Fix ANYTHING

Can accelerate damage to the joint

Inhibit good cells and healing

These medication are COUNTERPRODUCTIVE

SurgerySurgery is necessary is some situationsCould it be done too often?Some common procedures have no benefit.

So is PRP Better?Uses your own blood components

No medications - nothing from a drug company

Provides a natural way to stimulate the body to heal damaged tissue

Balances the “environment” of the joint to reduce symptoms

Essentially no side effects

What Does PRP Do In an Arthritic Joint?

Rebalance environment

Improves lubrication properties

Stimulates cartilage survival and repair

Mobilizes stem cell migration

Restabilize an unstable joint

PRP Intra-articular Pathways

Decreases BAD molecules - MMP, IL - reduces CATABOLIC PROCESSES

Increases GOOD molecules - TGF, TIMP, IRAP, A2M

REBALANCES the micro-environment of the joint - back to favoring the normal healing status

PRP Stimulates Hyaluronic Acid Production

Produced by synovial cells

Important for lubrication/viscosity of joint fluid

Hyaluronic Acid - Hyaluronan

Viscosupplementation - Synvisc, Orthovisc - from rooster combs

HA alone not enough to protect the joint

PRP Stimulates Lubricin (Proteoglycan 4) ProductionLubricin - other names Superficial Zone Protein

(SZP), Proteoglycan 4 (PRG4)

Incredible lubricating qualities

When joint compressed - repels surfaces

Acts synergistically with HA to reduce friction and protect the joint surfaces

Expression of PRG4 gene stimulated by the GF’s in PRP

All of this is inhibited by NSAIDS and corticosteroid

Supplementing Joint with HA alone is not enough! (Without Lubricin, HA is useless)

Lubricin molecules on cartilage surface push

the surfaces apart apart

PRP Reduces Cartilage Breakdown

Reduces cartilage breakdown - Am J Sports Med 2015Early PRP inhibits cartilage cell injury - Arthroscopy 2015PRP stimulates Anabolic molecules - Vet Med Int 2015

So Which Do You Choose?Treatment that temporarily improves symptoms, BUT causes more problems

OR, treat the joint in a way to rebalance and heal it, naturally, the way it was meant to be.

Avoid complication

Avoid Surgery

Ligaments and Tendons

What Happens in Ligaments and Tendons?

Balance: Repair vs. BreakdownREPAIR

healthy tenocytes/fibroblasts

matrix remodeling

organized fibers/structure

good vascularity

BREAKDOWN/DEGENERATION

unhealthy cells

poor remodeling with degeneration

poorly organized fibers

poor vascularity

Ligament and Tendon Injuries -What happens to these structures when injured?

What Happens When a Ligament/Tendon Is Injured?

Macro or Micro TearsCan get bleeding in the substance of the tear Less bleeding with tendon than with ligaments Bleeding initiates a healing cascade

Phases of HealingInflammatory Phase - local chemicals released - few days

Repair Phase - mediated by blood clot/platelets - new cells - new blood supply - few weeksRemodeling Phase - transitions Type 3 to Type 1 collagen - more organized - few months

What If Healing Does Not Progress?Poor

environment/poor vascularityThings get stuck in the inflammatory phase

Or stop in the early repair phase

Pain, Inflammation, non-healing persist

Structure is weak - poor integrity - poor function

What Does Traditional Treatment Do To Ligaments

and Tendons?Rest/ImmobilizationNSAIDSCorticosteroidsSurgery

ImmobilizationStiffness

Muscle atrophy

Weakens ligaments and tendons

Bone decalcification

COUNTERPRODUCTIVE

NSAIDSAll their side effectsInhibit inflammation - 1st phase of healingInhibit repair mechanismCOUNTERPRODUCTIVE

Corticosteroids

Inhibit inflammation - important component of healing

Inhibit repair - detrimental to stem cells/tenocytes/fibroblasts

Weaken ligament and tendon - additional ruptures/tears

COUNTERPRODUCTIVE

SurgeryInvasive

Denudes entire area of its native blood supply

Massive scaring/adhesions

Alters normal anatomy/function

THEN has to go through all phases of healing - all over again

COUNTERPRODUCTIVE

How Does PRP Work in Treating Ligaments and

TendonsRe-initiate inflammatory phase

Stimulates repair phase -

release of multiple growth factors

stem cell migration - fibroblasts/tenocytes

Balance inflammation/anti-inflammation and reduce pain pathways

Non-invasive/maintains anatomy/function

So Which Do You Choose?

Treat in ways that could create more adverse effects - stiffness, impairment, long recovery

Use medications that reduce pain and inflammation, but inhibit healing

Or, treat the injury with a product that stimulates the normal healing process, is non-invasive, maintains normal anatomy

Avoids complications, avoids surgery

Comparing:Traditional vs. PRP

Traditional: hides pain, shuts down healing, complications, paves the way to more injury and surgery

PRP: Rebalances natural healing/repair environment, paves the way to cure

Some Problems That PRP Treats Very Well

Knee Arthritis

Shoulder Impingement

Lateral Epicondylitis

Wrist Arthritis/Ligament Injuries

Ankle Sprains

Plantar Fasciitis

Knee ArthritisCartilage deteriorationInflammatory environmentCatabolic environmentPoor lubricationPain pathways

Arthroscopic Debridement for Painful Arthritic Knee - With

Meniscal TearOne of most common surgeries done

Studies:

Incidental meniscal tears - no relationship between tear or cartilage loss and symptoms

Meniscal surgery patients did no better than those who had no surgery and PT - NEJM 2012

Surgery has no benefit over “sham” (even with mechanical sx)- Annals of Int Med 2016

Menisectomy causes increase forces and a more rapid progression of arthritis - J Biomech 2014

Knee Joint Replacement10 million people in US have Knee OA$30 Billion spent annually on Knee Replacements alonePerhaps need a new paradigm for Knee OATry to delay or prevent people from needing joint replacement

Can Knee Arthritis Be Slowed Down?

More effective than viscosupplemenation - J Arthroscopy 2015

Reducing the rate of cartilage wear and tear- HSS 2013

Reduces cartilage breakdown - Am J Sport Med 2015

Inhibits cartilage cell injury - Arthroscopy 2015

Stimulates ANABOLIC pathways/molecules - Vet Med Int 2015

Platelet Rich Plasma

Shoulder ImpingementRotator cuff tendons weaken, develop tears, degenerative changes

Poor blood supply

Unable to heal itself

Gets stuck in early phase of repair

Chronic changes, inflammation, pain

Poor healing environment

Shoulder Impingement

NSAIDS - minimal benefit, inhibit healing

Corticosteroids -

if used - no longer see healing response - Br J Sports Med 2014

kill rotator cuff cells - Bone Joint Res 2014

Shoulder ImpingementSurgery - Acromioplasty

structures - bone and ligaments - with pain = without pain

Altering bony and ligamentous structure DOES NOT LEAD TO SYMPTOM IMPROVEMENT

JBJS Am 2011

Shoulder Impingement - PRPPRP more effective than corticosteroid

in pain relief (30% better)

in ROM improvement (3X more improvement)

16X less likely to undergo surgery (3/100 vs 48/100)

O’Donnell, et al. AAOS 2013

Lateral EpicondylitisCommon Extensor tendon becomes weakened, tears, degenerative changes (really a tendinopathy)

Poor blood supply

Gets stuck in early phases of healing

Chronic changes, inflammation, pain

Poor healing environment

Lateral EpicondylitisNSAIDS - minimal benefit, inhibit healing

Corticosteroids -

inhibit healing process

can additionally weaken the tendon

fat and skin atrophy

Corticosteroid actually WORSE than NO TREATMENT at 6 months and beyond

WHAT ARE WE DOING????????Orthopedics 2010

Lateral Epicondylitis - PRP

PRP provides excellent and superior results

Results are longer lasting

Particularly better than corticosteroid injection

Am J Sports Med 2006, 2014, J Clin Diag Res 2015, J Hand Microsurg 2015

Lateral Epicondylitis - PRP Compared to Surgery:

PRP - showed 83% improvement

Surgery - showed 46% improvement

PRP improved 2X as much as surgery

SO WHY ARE WE STILL DOING SURGERY FOR THIS PROBLEM? J Orthopaedics March

2016

Wrist and Thumb ArthritisInstability is a hallmark

Progressive Degeneration

Traditional Treatments -

Corticosteroids -

Surgery -

Wrist and Thumb Arthritis - PRP

Treat all inherent problems:

arthritic joint - balance environment

instability - balance ligaments

nerve issues

Wrist TFCC Tear/Ligaments Tears

TFCC degenerative tears similar to problem with meniscal tear

Same issues

Structural abnormality does not correlate with symptoms

Questionable how much debridement help

PRP rebalances joint environment/improves stability

Ankle SprainsImmobilization - stiffness, atrophy

NSAIDS/Corticosteroids - inhibit healing, weaken structures

Surgery - try to avoid

PRP

more rapid return to activities (1/2 the time)

better stability and pain (2X improvement)

AAOS Now 2014, Knee Surg Sport Traum 2015)

Plantar FasciitisTear/degenerative changes at plantar fascia origin

Poor blood supply/chronic changes/inflammation

Stuck in early phases of repair

PRPmore effective and durable than corticosteroid3X (300%) the functionality and improvement of painActually heal structures - rather than mask Sx

(Foot Ankle Int, April 2014)

Stem Cell Therapy

Bone Marrow Aspirate

Adipose Derived Stem Cells

A more “potent” form of PRP.

(Not amniotic products)

The body needs to express itself.Traditional medicine has suppressed the body’s healing ability.

Orthopedic Regenerative MedicineAllows the body to heal itself

PRP is a way to treat many musculoskeletal problems

Interventional Orthopedics will continue to grow

Will be able to replace many types of current therapies

BRIGHT FUTURE