Bioventus EXOGEN Guia Del Usuario página 26

Apart from Handolin et al.
19-20
above used ultrasound intensity levels ranging
from 0.5 W/cm to 2 W/cm and no untoward
2 2
effects were noted. These intensities are 16 to 60
times higher than the intensity used in the
EXOGEN Ultrasound Bone Healing System. It is
reasonable to conclude that metal present in a
healing fracture would not affect the safety or
effectiveness of the EXOGEN Ultrasound
Bone Healing System.
e. Clinical
No device-related adverse reactions or medical
complications related to the use of EXOGEN
have been reported during the clinical
studies .
2-11, 19, 21-37
Mode of Action
a. Mode of Action
The low-intensity pulsed ultrasound delivered by
the EXOGEN Ultrasound Bone Healing System is
a mechanical stimulus. This has been clearly
demonstrated by experimental work on cadavers
in which tissue around an osteotomized bone
moved in response to the ultrasound signal at a
frequency of 1kHz, the same frequency as the
pulse of the EXOGEN ultrasound signal. Tissue
motion has been calculated to be of the order of
0.5nm, approximately 1000 times less than
"micromotion." As well as soft tissue movement,
it was demonstrated that the bone moved albeit
on a smaller scale . This work shows stimulation
38
with the EXOGEN Ultrasound Bone Healing
System provides motion on a nanometer scale,
suggesting the mode of action is independent
of fixation methods such as casting or external
fixation. Mechanical energy is transformed into
biochemical energy by transduction at the cell
membrane. One family of cell membrane
receptors that are responsible for this transduc-
tion are integrins. It has been demonstrated that
the EXOGEN ultrasound signal stimulates cells
through an integrin pathway
39
pathway, cytoskeletal organization, transcription
factor activation, gene upregulation, protein
synthesis and increased cell proliferation have
all been observed.
23
the studies reported b. Review information on fracture healing
and bone formation
Two review articles
and basic science evidence for the EXOGEN
Ultrasound Bone Healing System. Their analyses
suggested the EXOGEN Ultrasound Bone
Healing System induced cellular reactions at
each phase of fracture healing from inflammation
through to endochondral ossification
a number of preclinical studies have shown
acceleration of bone healing with the EXOGEN
Ultrasound signal and increased mechanical
properties at the fracture site. Pilla et al.
two rabbit bilateral fibular osteotomy place-
bo-controlled studies, reported statistically
significant acceleration of ultrasound treated
fibulae versus the placebo side 1.7 and 1.4 times
faster, respectively. Wang et al.
reported on ultrasound fracture treatment in a
model of bilateral closed femoral shaft fractures
made in rats and stabilized by a Kirschner wire,
serving as an intramedullary rod. Ultrasound
treated fractures were shown to be significantly
stronger and stiffer than the controls, showing
that the stimulatory effect of ultrasound on
fracture repair was not inhibited by the presence
of a metallic internal fixation device.
Azuma et al.
micro-computed tomography, were able to
determine that accelerated fracture healing in
the ultrasound-treated group was typical of
normal bone healing. EXOGEN Ultrasound
accelerated early, mid and late stages of fracture
healing with maximum impact achieved when
applied throughout the healing process. Takikawa
et al.
45
Ultrasound Bone Healing System in a hypertro-
phic non-union model demon-strating 50%
resolution in the active group versus 0% in the
control group at 6 weeks.
c. Modes
Effects on chondrocytes—Chondrocytes have
. Within this integrin
been shown to respond to the EXOGEN signal
by an increase in proteoglycan synthesis
(mediated by calcium signaling) and the
increase in aggrecan mRNA
have assessed the clinical
25,40
. In addition,
33
and Yang et al.
42
, through histological analysis and
44
studied the impact of the EXOGEN
.
43,46
Response of marrow cells to the EXOGEN
ultrasound signal—The EXOGEN signal
accelerated the differentiation of mesenchymal
cells when cultured in a system designed to
promote chondrocytic differentiation
Periosteal cell response—Human periosteal cell
cultures responded to low intensity pulsed
ultrasound by increasing expression of alkaline
phosphatase, osteocalcin and VEGF. In addition
long term treatment (4 weeks of 20-minute daily
treatment) increased the level of mineralization
in these cultures
in
34,41
Osteoblast differentiation—MMP13 and alkaline
phosphatase are two enzymes key to the process
of mineralization. Unsworth et al.
an increase in both these enzymes in MC3T3-E1
cultures after stimulation with EXOGEN ultra-
43
sound. Further evidence that ultrasound affects
the mineralization process comes from Saito et
al. who demonstrated accelerated calcium
50
accumulation in MC3T3-E1 cultures. Significant
increases (8.6-fold and 3.6-fold higher than
untreated controls) were seen at day 25 and day
35 respectively. Collectively the findings of these
studies demonstrate that in a pre-osteoblastic
culture system EXOGEN low intensity pulsed
ultrasound accelerates differentiation along the
osteoblastic lineage. Animal studies have shown
that such effects in a fracture environment can
benefit the formation of a mineralized callus,
stabilizing the fracture and increasing the strength
of the bone.
Clear evidence exists that the EXOGEN
Ultrasound Bone Healing System accelerates the
healing process at all stages of fracture repair
In-vitro evidence supports this by demonstrating
effects on various cell types, stimulating proteins
involved in various biological processes and
demonstrating acceleration of some processes
in organ culture.
.
47
.
48
demonstrated
49
44,51
.