04/12/2016

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Balloons, Boing-Boings, and Bioreactors

A Story of Knee Osteoarthritis

David Crane MD

Bluetail Medical Group St. Louis, MO; Columbia, MO; Naples, FL

Disclosures

• Consultant for Arthrex

Bluetail Medical Group

• Non-operative sports medicine

• Percutaneous use of biologics

• Collaborate closely with surgeons

– Intra-operative use

– Post-operative use

• Over 24,000 patients treated to date

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Biocellular Graft Use

• Follow FDA guidelines

• Minimal manipulation

• Point of care

• Most common treated disease

• Knee Osteoarthritis

• A blind doctor walks into a bar….

• And finds way more than he bargained for!

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What I’ve learned since fellowship

There is a

balloon…

What I’ve learned since fellowship

There is a

boing boing…

What I’ve learned since fellowship

There is a

bioreactor

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These 3 roughly correlate to;

Mechantransduction of

the joint capsule

And neurohormonal

signalling

And myotendionous

support

These 3 roughly correlate to;

Hoop stress of the

meniscus

AND

mechanotransduction

of cartilage

These 3 roughly correlate to;

Synovium with:

Growth Factors

Progenitor Cells

HA

Chemokines,

Cytokines,

Interleukins

MMP’s

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The Capsule

Mechantransduction of

the joint capsule

Capsular Anatomy

Capsular Anatomy

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Capsular Anatomy

Transverse section of the

medial joint capsule above

the level of the joint line:

Layers I and II are fused

anteriorly

Layers II and III are fused

posteriorly

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Capsular Anatomy

Capsular Anatomy

Capsular Anatomy

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Capsular Anatomy

Capsular Anatomy

The Meniscus and Cartilage Interface

Hoop stress of the

meniscus

AND

mechanotransduction

of cartilage

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Meniscus Anatomy

• Load and forces are distributed across a much larger surface area because of the menisci, which:

• (1) decrease focal contact pressure by increasing the contact area

• (2) protect the underlying articular cartilage. Resection of 15-34% of a meniscus may increase contact pressure by more than 350%. Normal knees have 20% better shock-absorbing capacity than meniscectomized knees.

Insall JN, Scott WN, eds. Surgery of the Knee. 3rd ed. Philadelphia, Pa: WB Saunders Co; 2001.

Rodkey WG. Basic biology of the meniscus and response to injury. Instr Course Lect. 2000. 49:189-93.

Vaziri A, Nayeb-Hashemi H, Singh A, Tafti BA. Influence of meniscectomy and meniscus replacement on the

stress distribution in human knee joint. Ann Biomed Eng. 2008 May 22. epub ahead of print.

Three layers of the

medial capsule:

I. Crural fascia

II. Superficial portion

of the MCL

III. Deep portion of

the MCL including

the

meniscofemoral

and meniscotibial

extensions of the

deep MCL.

The Synovium and Fat Pad

Synovium with:

Growth Factors

Progenitor Cells

HA

Chemokines,

Cytokines,

Interleukins

MMP’s

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Why mixed results with cellular

treatments?

• Many variables exist in product & delivery ere are many variables in product and delivery

Platelet Activation

Activation releases > 1500 proteins

• Alpha granules contain > 300 growth

factors

– PDGF, VEGF, TGF-β1, bFGF, EGF

• Dense granules contain serotonin,

histamine, Ca, adenosine and dopamine

Unactivated platelets

Activated platelets

Growth Factors

• Anti-inflammatory

• Anti-degradative

• Analgesic

• Antimicrobial

• Modulate healing

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Rationale for PRP in OA

• PRP Chondrocyte proliferation

Chondrogenic markers

Col 2, PG Synthesis

Cartilage repair- PDGF and TGF

MSC proliferation

Inhibition of pain pathway

Synovial HA Production

Rationale for PRP in OA–ACP

vs HA

• ACP MMP-13

• ACP HAS-2 expression in synoviocytes

• ACP cartilage synthetic activity

➔ACP acts to stimulate endogenous HA production and decrease cartilage catabolism

} Compared with HA

Sundman et al, 2014

Mechanism of Action for

OA:ACP

Cartilage and synovium co-culture model

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Mechanism of Action for

OA:ACP

Cartilage and synovium co-culture model

Sundman et al., 2014

Mechanism of Action for

OA:ACP

• Controlled Laboratory

Study

• Investigated proliferation

of Superficial Zone

Protein (SZP) and cell

proliferation at articular

cartilage after contact with

ACP

Sakata et al, 2015

Level 1 Evidence PRP vs HA for

OA

Plasma based PRP versus HA:

• WBC preparation

• RCT - 176 patients 3 weekly injections

• 38% of patients receiving PRGF had 50% decrease in

WOMAC pain score in 24 weeks vs 24% of patients

receiving HA (p value 0.044)

Sanchez et al, 2012

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96 patients:

PRGF 3 injections vs 1 injection HA

PRGF (Plasma Rich in Growth Factors- WBC) vs HA:

PRP Superior to HA for up to 12 months

Level 1 Evidence PRP vs HA for

OA

Vaquerizo et al, 2013

ACP Superior to HA for up to 6 months

Level 1 Evidence ACP vs. HA for

OA

Cerza et. al, 2012

Double Blind Level 1 ACP vs HA

0

10

20

30

40

50

60

70

1 2 3 4 5 6

IKD

C S

core

Visit

IKDC*

ACP

HA

ACP Clinically Superior to HA at 6 months

0

1

2

3

4

5

6

7

1 2 3 4 5 6

VA

S Pa

in S

core

Visit

VAS Pain*

ACP

HA

Cole BJ, Fortier L, Karas V, Merkow D, Stuckey A, Butty D, Verma N, Preliminary Data, 2014

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Double Blind Level 1 ACP vs HA

ACP Biologically Superior to HA at 6 months

0

0.05

0.1

0.15

0.2

0.25

1 2 3 5 6

Co

nce

ntr

atio

n

Visit

TNF-α

ACP

HA

0

2

4

6

8

10

12

14

16

18

20

1 2 3 5 6

Co

nce

ntr

atio

n

Visit

IL-6*

ACP

HA

Cole BJ, Fortier L, Karas V, Merkow D, Stuckey A, Butty D, Verma N, Preliminary Data, 2014

Level 1 Data Meta-Analysis

Chang et al, 2014

HA

PRP

Meta-Analysis WBC Effect 2015

• Compared WBC concentration (LR vs LP) on

efficacy

• Six RCT level 1 and three level 2

• LP-PRP results in improved functional

outcome- WOMAC and IKDC scores compared

with HA and placebo when used for treatment

of knee OA

• Adverse reactions to PRP may not be directly

related to leukocyte concentration

Riboh, 2015

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Systematic Review PRP for OA

• Six Level 1 Studies- 739 patients (817 knees)

• PRP showed significant clinical improvements compared to HA/saline up to 12 months

• WOMAC significantly better for PRP than HA 3-6 months (p=0.0008); 6-12 months (p=0.0062)

• 5 of 5 LP-PRP studies showed improvement!

• Filardo (LR-PRP) showed no improvement

Meheux, 2015

Meta-Analysis of PRP

Meta-Analyses

• Level IV systematic review

• Concluded that intra-articular PRP is a

viable treatment for knee OA

– Particularly with early degenerative changes

• Shown to be more effective than other strategies-

including HA or placebo treatments

Campbell, 2015

Putting it all together….

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BMC – Bluetail Evaluation of Samples

• Samples from 11 patients

• All BMC drawn PSIS

– Same operator

– Same technique

• Evaluated at outside labs for cell ct & culture

– Previously validated shipping method

46

47

Pt. 1 at 48 hrs.

BMC BMA

CFU CFU Colonies are

easy to spot

and count

Pt. 1 at 72 hrs.

48

BMC BMA

Colonies become more

difficult to distinguish

from one another

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Pt. 1 at 96 hrs

49

BMC BMA

Colonies blend together

50

Bone Marrow Aspirate

Angel BMC

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We found what we expected

Cellular

Concentrations2% BMC/PPP

Statistical

Difference?15% BMC/PPP

PLT (k/μL) 145 ± 193 Yes, p = 0.016 1030 ± 732

WBC (k/μL) 1.90 ± 3.54 Yes, p = 0.002 52.87 ± 28.34

NE (k/μL) 0.16 ± 0.23 Yes, p = 0.023 17.13 ± 15.43

LY (k/μL) 0.95 ± 2.06 Yes, p = 0.001 18.20 ± 9.32

MO (k/μL) 0.35 ± 0.69 Yes, p = 0.002 7.02 ± 3.87

RBC (M/μL) 0.04 ± 0.01 Yes, p = <0.001 1.51 ± 0.65

TNC (k/uL) 2.22 ± 4.10 Yes, p = 0.002 56.98 ± 30.23

HPC (k/μL) 2.00 ± 4.47x10-4 No, p = 0.198 2.92 ± 5.09x10-2

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IL-1ra Average ± StDev (pg/mL)Statistical

Difference?

2% BMC/PPP 1693 ± 1012

15% BMC/PPP 22654 ± 3877

IL-1beta Average ± StDev (pg/mL)Statistical

Difference?

2% BMC/PPP 8.8 ± 1.6

15% BMC/PPP 24.6 ± 35.0

Yes, p = <0.001

Yes, p = 0.041

But found something unexpected!

There is IL-ra in BMC!

IL-ra1 and BMC

• A ratio of IL-ra/IL-1β of 10-1000:1 is sufficient

to effect blockade of the IL-1 receptors,

thereby alleviating the degenerative effects of

IL-1

Wehling et al 2007

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IL-1ra/IL-1beta Ratio AverageStatistical

Difference?

2% BMC/PPP 193.5

15% BMC/PPP 720.6Yes, p = 0.007

Clinical Outcome of Bone Marrow Concentrate in Knee

Osteoarthritis. Oliver, Bayes, Crane; J of Prolo: 2015

• Prospective Case Review using Arthrex SOS

– 70 pts with II-IV Knee OA

– BMC and MM Adipose

– VAS and KOOS at 3 and 6 months

• Stat. significant improvement

– Pain

– Function

– QOL

– ADL’s

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Same Case Review carried out to 1 year

– 312 pts with II-IV Knee OA

– BMC and MM Adipose

– % Compliance

– Pre-tx 98.7 (305)

– 3 mo 96.2 (205)

– 6 mo 98.8 (170)

– 1 yr 100 (87)

– VAS and KOOS at 3,6 and12 months

• Stat. significant improvement in all measures

Angel BMC Knee OA

SOS Data - VAS

Pre-surgical 4.98

3 months 3.05

6 months 2.72

1 year 2.89

(-2.09)

Angel BMC Knee OA

SOS Data - KOOS Pain Scale

Pre-surgical 54.4

3 months 69.3

6 months 71.4

1 year 73.6

(+19.2)

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Angel BMC Knee OA

SOS Data – KOOS Symptoms Scale

Pre-surgical 53.2

3 months 69.7

6 months 69.9

1 year 70.7

(+17.5)

Angel BMC Knee OA

SOS Data - KOOS ADL’s

Pre-surgical 60.6

3 months 73.4

6 months 78.3

1 year 78.6

(+18)

Angel BMC Knee OA

SOS Data – KOOS Sports/Rec

Pre-surgical

33.6

3 months

48.6

6 months

48.4

1 year

51.3

(+17.7)

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Angel BMC Knee OA

SOS Data – KOOS QOL

Pre-surgical 29.1

3 months 47.9

6 months 50.8

1 year 52.6

(+23.5)

• Biocellular grafts are showing continued

promise as a viable, safe, effective, and cost

effective way to treat mild to moderate and

possibly some cases of severe OA in some

cases.

• Choose your patients wisely

• “Go out and do good in the world”

Summary

Thank You!

David Crane MD

dcranemd@gmail.com

Bluetail Medical Group St. Louis, MO; Columbia, MO; Naples, FL