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
1.2
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Koh Laboratory (unpublished data)Department of Kinesiology & Nutrition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Koh & Judex, 2013, unpublished data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
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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
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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
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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
C
D
Acce
lera
tion
(g, p
eak-
peak
)
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0.30
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
1.0
1.5
2.0
2.5
3.0
3.5
Lum
ber S
pine
BM
C (g
)
Control LIV
Lumbar Spine BMC
1.9% tx difP<0.05
0
1
2
3
4
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
4
6
8
10
Perc
ent C
hang
e fro
m B
asel
ine
Placebo LIV
3.1% tx difP<0.01
Tibial StiffnessTibial Strength
0
2
4
6
8
10
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
-3
-2
-1
0
1
2
3
4
5
6
Control VibrationP
erce
nt C
hang
e
3.2% tx difP<0.04
n=24 n=24
0
1
2
3
4
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
3
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?