Low Intensity Vibrationas a Non-Drug Intervention for

Musculoskeletal Injuries and Disease

November, 2014The Scientific Basis of LIV Therapy

Clinton Rubin, Ph.D.SUNY Distinguished Professor & ChairDepartment of Biomedical Engineering

Stony Brook University, New York

Chief Scientific OfficerMarodyne Medical, Inc.

Wolff’s Law: Form follows function in bone….

…lose up to 2% per month…

35% more bone in playing arm

Jones et. al. 1977 Lang et. al., 2004

Muscle

Type IIb

CORR; 2006

M; Age 25

M; Age 63

Contractile spectra of postural muscle

Huang et. al., J. Geront. 1999

Does fibre-type specific sarcopenia suppress regulatory signals to bone?

Mechanicalcontent in

20-50 Hz band

deteriorates as a function of age

LIV influences on the musculoskeletal system

0.0

0.2

0.4

0.6

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1.0

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1.4

BC AC WBV

Cros

s se

ctio

n ar

ea [m

m2 ]

a

b

0

200

400

600

800

BC AC WBV

Tota

l fib

er n

umbe

r

(mean+SD, n=12)

A.

ATPase staining (pH10.4)w/ Type II as black300µ

Lie et. al., 2008>30% increase in cross-sectional area of muscle (p<0.05), trend of increase in fiber # and area

AC WBV

Young Mice Old Mice

Control LIV

LIV promotes Force:Muscle activity In collaboration with Dr. James Bibb, UTSW

Bibb et al., 2014; J. Biomechanics, In Press

LIV augmentation of muscle healing following laceration injury

Koh Laboratory (unpublished data)Department of Kinesiology & Nutrition

Center for Tissue Repair & RegenerationUniversity of Illinois at Chicago

H&E

14 days post-injury

H&E

Trichrome

Koh & Judex, 2013, unpublished data

Deterioration of Balance andPostural Stability as a Result of

Chronic Bed Rest

And increased susceptibility to falls

(similar to instability in the aged)

Baseline

Day 90 Bed Rest

0102030405060708090

100

Max Forward Sway Max Backward Sway RMS Sway

% C

han

ge p

er

Mo

nth

Control (n = 11)Vibe (n = 17)

0

20

40

60

80

100

120

140

160

Max Forward Velocity Max Backward Velocity Max Resultant Velocity RMS Velocity

% C

ha

ng

e p

er

Mo

nth

Control (n = 11)Vibe (n = 17)

LIV retention of postural stability Muir et. al., Gait & Posture, 2011

Bone

Osteoporosis: Reduced bone quality & quantity elevates fracture risk

20y 40y

60y 80y

Expansion of the marrow space by fat…

Bone can be maintained with a few large loadingcycles, or thousands of extremely small ones

maintain

resorb

anabolic

Qin et. al., JOR, 1998

Delivering mechanical signals to the skeleton

0 0.1g 0.2g 0.3g 0.9g0

10

20

30

40

50

60

% L

abel

ed S

urfa

ce

Acceleration

Tibia Femur

Labeled Surface

0.0 0.5 1.0 1.5-95

-90

-85

-80

-75

-70

Mic

rost

rain

Time (seconds)

3 microstrain induced in the turkey tibia, 30Hz @ 0.3g

Can exercise stem this musculoskeletal deterioration?

Rosen & Bouxsein, Nat. Rev. Rheum, 2006

45% increase in trabecular bone volume 12% increase in stiffness27% increase in strength

Rubin et. al., Nature, 2001

experimentalcontrol

Hwang et. al., 2009

Enhancing bone regeneration with extremely small accelerations

Baseline 4 weeks 8 weeks

0.4g45Hz

20min/d

Control

In vivo µCT scans of 5mm defects in the rat cranium

Regenerate:Area: +181% Vol: +137%Th: +53%

Control 30 Hz

Tors

iona

l Stif

fnes

s (N

m/d

eg)

0

10

20

30

40

50

60

P < 0.05

Control 30 Hz

Augmentation of healing fractures by low level signals(30Hz, 25 micron displacement on sheep tibia)

30 Hz0.0

0.1

0.2

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0.5

0.6

Locomotion

Disp

lace

men

t (m

m)

Goodship et. al., JOR, 2009

Rubin et. al., Spine, 2003

Transmissibility of low-level signals to hip and spineIn collaboration with Dr. M. Pope & T. Hansson, Gothenburg, Sweden

Æh

Æs

0

50

100

150

200

250

Standing 20 15 10 5

% T

rans

mis

sio

n

Table Angle (degrees)

Effect of Table Angle on Transmission

Delivering the LIV signal to a subject in a standard hospital bed

US Army Grant currently under review for the use of the LIV technology in the suppression of bone loss and adiposity gain in SCI

subjects

Is it safe? ISO-2631 Human Tolerance Limits for Vibration

-6

-4

-2

0

2

4

6

3 3.1 3.2 3.3 3.4 3.5Time (seconds)

Acc

eler

atio

n (g

)Power PlateJuvent Plate

Safe > 4 hours Safe < 1 minute

Acceleration exposure of PowerPlate v. Marodyne device

FDA has concluded LIV signal a “non-significant risk device”

1.25 2.0 3.5 5.0 8.0 12.5 20 30 50 80

Frequency (Hz)

16 hours

8 hours

4 hours

1hour

30 minutes

1 minute

A

B

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D

Acce

lera

tion

(g, p

eak-

peak

)

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0.50

0.75

1.25

2.00

3.00

5.00

10.00

15.00

4.00

Is it safe? ISO-2631 Human Tolerance Limits for Vibration

Muir et. al., JSMS, 2013

Inhibition of bone loss in a post-menopausal populationIn collaboration with Drs. R. Recker & D. Cullen, Creighton University

One year, 20 m/d, 30Hz @ 0.2g

-4

-3

-2

-1

0

1

2

**

*

Per

cent

Cha

nge

in B

MD

Placebo Active

Spine L1 Femur Troch

-4

-3

-2

-1

0

1

2 Women < 65Kg Women > 65Kg

% C

ha

ng

e in

BM

D Placebo Active

*

Rubin et. al., 2004

Inhibition of osteoporosis in children with cerebral palsyIn collaboration with Drs. K. Ward & Z. Mughal, St. Mary’s Hospital, Manchester U.K.

20 subjects, mean age: 9.1y10 placebo, 10 active; 0.3g

Six Months, 4.4 minutes per dayWard et. al., JBMR, 2004

-18

-15

-12

-9

-6

-3

0

3

6

9

12

Cha

nge

in T

ibia

vT

BM

D (

mg/

ml)

17.7% tx dif. p=0.004

Placebo Active

Anabolic response to LIV in children with Duchenne Muscular DystrophyIn collaboration with Professor Maria Luisa Bianchi and Colleagues, Milan, Italy

Ambulatory, 9.3y + 3.9y, One year study, All treated w/ glucocorticoids

-20

-15

-10

-5

0

5

10

baseline 6 mos. 12 mos.

*

*

**

**

Bianchi et al., ASBMR 2013: poster LB-SU03

-6,00

-2,00

2,00

6,00

10,00

ACTIVE6 mos

ACTIVE12 mos

PLAC 6mos

PLAC 12mos

**

*

**** **

6 mos. 12 mos. 6 mos. 12 mos.LIV PLACEBOn=11 n=10

SpineFem. NeckTotal Body

% Change in Bone Mineral Density

LIV CTxLIV NTxPlacebo CtxPlacebo NTx

% Change in Bone Resorption Markers

* p<0.02 ** p<0.05

Promotion of bone density in Adolescent Idiopathic ScoliosisProfessors T.P. Lam, L. Qin & J. Cheng; Chinese University of Hong Kong

Lam et. al., Ost. Int. 2012

0.00

0.01

0.02

0.03

0.04

0.05

Cha

nge

in F

emor

al N

eck

BMD

(g/c

m2 )

Control LIV

Femoral Neck BMD

n = 61 n = 63

2.0% tx difP<0.01

149 AIS girls, 15-25y61 LIV; 0.3g, 30Hz

One year20 minutes per day

0.0

0.5

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1.5

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Lum

ber S

pine

BM

C (g

)

Control LIV

Lumbar Spine BMC

1.9% tx difP<0.05

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1

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5

Perc

ent C

hang

e fro

m B

asel

ine

Year One Year Two

Placebo LIV

Inhibition of bone loss in the frail elderlyIn collaboration with Drs. D. Kiel & M. Hannan, Harvard Medical School

Percent change from baseline ofTotal Femoral Trabecular Bone Density

N>50 per groupMeans + s.e.; nsd

Promotion of bone quality in end-stage renal diseaseIn collaboration with Professors M. Leonard and F. Wehrli, CHOP & U-Penn

Rajapakse et. al., ASBMR 2012

0

2

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8

10

Perc

ent C

hang

e fro

m B

asel

ine

Placebo LIV

3.1% tx difP<0.01

Tibial StiffnessTibial Strength

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2

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12

14

Perc

ent C

hang

e fro

m B

asel

ine

Placebo LIV

5.6% tx difP<0.01

Enhancement of the musculoskeletal system in young osteopenic women In collaboration with Dr. V. Gilsanz, Children's Hospital of Los Angeles, CA

Spine: Cancellous Bone Density

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-2

-1

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1

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Control VibrationP

erce

nt C

hang

e

3.2% tx difP<0.04

n=24 n=24

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1

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3

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5

6

Per

cent

Cha

nge

Control Vibration

3.8% tx difp=0.037

n=24 n=24

Spine: Area of Trunk Musculature

0

1

2

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4

5

Pe

rce

nt C

ha

ng

e

Control Vibration

2.99% tx difP<0.01

n=24 n=24

Femur: Cortical Bone AreaGilsanz et. al., JBMR, 2006

Can low mechanical signals influence fat metabolism?Young osteopenic women, 1y LIV

Inverse Interdependence of Bone and Fat Formation?

Bone Density Muscle Area Fat Area0

2

4

6

8

10

12

14

(mg/cm3) (cm2) (cm2)

Abso

lute

Chan

ge fr

om B

aseli

ne

Control LMMS

*

*

*

Luu et. al., JBMR 2009

“LIV is effective in fall prevention with improved muscle strength and balancing ability in the elderly”

Groups Fall %

Fracture%

Balance& Mobility

LIV = 364

66% avecompliance

18.6 1.1 Improved balance and muscle strength

Exercise = 346

Variance

28.7

P = 0.001

2.3

P = 0.171 P < 0.001

Leung et al, Osteoporosis Int, 2014

40 +65 yrs with unilateral throchanteric Fractures fixed with DHS or Gamma Nail

LIV Post Op Day 4 for 6mths0.3g 20 mins 7/785% compliance in LIV

Results: Control LIV

2 month

RANKL/OPG ratio 8.97+/-5.76

Positive QoL and RoM Hip P <0.516.26 +/- 13.22

Increase Hip BMD Non Fx sideFem neck loss -4.22%

Benefit 1.43%

-2.53%

Fracture Healing Early Fx impaction and IM callius

No Pain or problem using LIV device

Leung, ORS 2011

LIV enables wound healing in diabetic mice

H&E

CD31

7d post injury

Koh & Judex, 2013, unpublished data

H&E

CD31

Adiposity

Control Vibrated

10mm

Suppression of adiposity by low-level mechanical signals

Control LIV

27.6% less epididymal and 19.5% less subcutaneous fat (p<0.01)

BL6 male mice, 12w stimulation, normal diet

Prevention of diet induced obesity by mechanical signals

7w Male C57/BL6High Fat Diet for 12w

-28.5% visceral adipose tissue (p<0.02)

Leptin: -35.3% (p<0.05)

Adiponectin: -21.8% (p<0.01)

Liver TG: -25.2%p<=0.19

Liver NEFA: -19.2%p<0.02

LMMS

Control

Luu et. al., 2009

Adipocyte volume -38%DIO Liver @ 9 months; -28%

Luu et. al., 2010

Sedentary Bias Towards Fat

Biasing the Fate Selection of the Adult Stem Cell Population

Bone Volume:+13.3%P<0.01

Fat Volume:-25.4%

P<0.001

LIV Bias Towards Bone & Muscle

12w HFD

CT of Proximal

Tibia

CT ofAdipose

Burden inTorso

LIV Therapy biasing of MSC & HSC fate selection

X

+72%

-27%

Towards a stronger and healthier musculoskeletal system

XB-Cells

At six weeks: 37.2% increase in overall stem cell pool (Sca1+; p<0.03)46.1% increase in MSC pool (Sca1+ & Pref1+; p<0.02)

And promoting the bone marrow stem cell pool

Control LIV

0

5

10

15

20

25

30

35

CON LMMS

% S

ca-1

Pos

itive

Cel

ls

Total Stem Cells

+37.2%p=0.024

0.00.20.40.60.81.01.21.41.61.8

CON LMMS

%Sc

a an

d Pr

ef P

ositv

e Ce

llsMesenchymal Stem Cells

+46.1%p=0.022

Bone Marrow from CON Animal

Bone Marrow from LMMS

Animal

A B

C D

While Simultaneously Enhancing Bone Quantity & Quality

7w Male C57/BL6High Fat Diet

In vitro CT @ 14w

+7.3% bone volume in torso(p=0.055)

+13.3% bone volume in tibia (p<0.01)

+10.4% trabecular number (p<0.02)

-11.1% trabecular spacing (p<0.01)

-4.9% SMIP<0.02

LMMS

Control

Can LIV influence diabesity outcomes in mice that are already fat?

1

Suppression of obesity-induced osteoarthritis by LIV(Calcification of articular cartilage slowed by LIV)

Pamon et. al. 2013, unpublished data

Uncalcified Cartilage Thickness

Uncalcified + Calcified Region

Thic

knes

s (µ

m)

Thic

knes

s (µ

m)

RD HFD HFD+LIV

RD HFD HFD+LIVHigh Fat Diet +LIV

High Fat Diet

Regular Diet

Mechanical influence on mesenchymal stem cellsGFP+ recipients to track MSC differentiation

Control LMMS0

20

40

60

80

100

120

GF

P+ A

dip

ocyte

s / M

SC

's

Control LMMS0.00

0.05

0.10

0.15

0.20

0.25

0.30

Fa

t M

ass

(g)

*

B

0

20

40

60

80

100

120

140

Control LMMS

% G

FP

Eng

raft

me

nt

Epididymal Fat Pad-12.1%P<0.03

Lethal irradiation, marrow transplant, 6w mechanical stimulation

Epididymal Fat Pad GFP+ Adipocytes MSC Number-12.1% -18.9% +23.4%P<0.03 p<0.02 p<0.001

Epididymal Fat Pad GFP+ Adipocytes-12.1% -18.9% P<0.03 p<0.02

Low intensity vibration induces changes in cell architecture

Sen et. al, Stem Cells, 2011

Control 3h post 20 minutes LIV

But these adaptations are transient

24h post-LIV

Low Intensity Vibration can regulate bone mass and

morphology

• Omnipresent signal in the skeleton• Targets bone cell progenitors• Stimulate bone formation• Suppress bone resorption• Produce lamellar bone• Self-targeting• Self regulating

• Non-drug prevention and/or treatment for osteoporosis?