General
The
main field of research in the laboratory is regeneration
processes in the skeletal muscle, heart muscle and
bone following trauma or Ischemic injury.
Recently
we have found that application of low energy laser
irradiation (LELI) to the site of injury in all the
above systems has been beneficial. The irradiation,
as applied, does not heat the tissue and has not been
found to cause side effects.
Research
Accomplishments
Augmentation
of skeletal muscle regeneration following injury to
toad and rat muscles by applying low energy laser
irradiation to the injured site has been established
in two in vivo models. A 2-and 8-fold increase
in rate of regeneration was achieved in rats and toads,
respectively. These studies demonstrate for the first
time such a profound enhancement of muscle regeneration
by any factor. This phenomenon has been partially
attributed to significant enhancement in the formation
of new blood vessels in the injured zone following
laser irradiation and significant promotion of the
satellite cells (stem cells of muscle regeneration).
The
possibility that the laser also affects satellite
cells in the injured zone was investigated by establishing
tissue cultures of isolated satellite cells from rat.
We showed that satellite cell proliferation is enhanced
2-fold by the laser, and that differentiation in
vitro is affected as well. Furthermore, laser
irradiation induced early cycle regulatory protein
synthesis due to activation of early cell cycle regulatory
genes. The effect of laser irradiation on cell proliferation
was established by demonstrating induction of cell
cycle regulatory genes and induction of MAP-kinase
family through the c-met receptor.
Laser
irradiation was found to enhance bone repair about
2-fold in an in vivo model via enhanced
differentiation of osteoblasts and their calcium deposition.
This phenomenon was further supported by direct irradiation
of human osteoblasts in tissue culture, which significantly
promoted their proliferation and differentiation in
vitro .
Bone
growth to metal implants was enhanced by heat treatment
of the implants (approved patent of this procedure)
and tested in large animals (goats) as a preclinical
model. A 2-fold enhanced fixation of the treated implants
was achieved over the non-treated implants.
In
the last 5 years the effect of laser irradiation was
also investigated on the infarcted heart. We have
demonstrated that following myocardial infarction
in both rats and dog’s reduction of 50%- 70% in infarct
size was achieved when the infarcted area was laser
irradiated with defined energy density. Furthermore,
desmin (myogenic marker) positive cells were more
numerous and ATP content higher in the laser irradiated
area of the infarcted myocardium. The above phenomenon
is novel. This extent of reduction of scar tissue
formation has not been achieved previously by any
drug or growth factors. The phenomenon has been published
in several papers including the most reputable journal
in cardiovascular research - Circulation .
Recently,
we have also found that laser irradiation caused a
rapid elevation in inducible heat shock proteins (HSP-70),
(which have been demonstrated in the past to have
cardioprotective effect in transgenic mice overexpressing
these proteins.) and angiogenesis. Thus, we demonstrated
the elevation of HSP- 70 in vivo
for the first time by a factor other than heat. This
could explain the salvage of the cells under acute
ischemic conditions. Furthermore, it also sheds light
on the possible mechanism of action of low energy
lasers in general.
Current
Research
Further
studies to explore the cellular mechanisms associated
with the biostimulatory effects of the low energy
lasers and, in particular, the mechanism associated
with the beneficial effects of laser irradiation on
cell survival under ischemic conditions and angiogenesis
both in skeletal and cardiac muscle. For that purpose
expression of proteins of the heat-shock family in
the ischemic heart and skeletal muscles is investigated.
The information accumulated on the above phenomenon
may prove of great significance to the possibility
of salvaging cells under ischemic conditions in various
diseases, pathologies and injuries. Thus, it may also
have direct clinical relevance since the laser energy
can be delivered to various organs via fiber optics.
In vitro systems of satellite cells and cardiac
cells will be used in addition to animal models to
further explore the molecular mechanism and signal
transduction pathways associated with the effect of
the low energy laser that has already been established
in our laboratory in vivo.
Cells
of skeletal muscle origin will be used for implantation
into ischemic myocardium to achieve a better performance
of the heart muscle post infarct or under chronic
ischemia. The cells will be irradiated with low energy
laser in vitro and post implantation to increase
their survival rate. In addition a recent project
is aimed to explore the possibility to induce stem
cells in the bone marrow by low level laser in the
infracted rat model. A follow up on the induced cells
in the blood (by FACS analysis) and in the targeted
organs will be performed.
This
is a novel approach that may shed light on the general
field of cell transplantation into organs to improve
function of ischemic/injured organs.
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Publications
(last 9 years)
1. T.Wolf, L. Gepstein, G. Hayam, A. Zaretsky, R.
Shofty, D. Kirshenbaum, G.Uretzky U.Oron, and S.A.
Ben-Haim. Three dimensional endocardial impedance
mapping: a new approach for myocardial infarction
assessment. Am. J. Physiol. 280: H179-H188. 2001.
2. U. Oron, T. Yaakobi, A. Oron, D.Mordechovitz, R.
Shofti, G. Hayam, U. Dror, L. Gepstein, T. Wolf, C.
Haudenschild, and S.A. Ben Haim. Low energy laser
irradiation reduces formation of scar tissue following
myocardial infarction in rats and dogs. Circulation
103: 296-301.2001.
3. G. Shefer, M. Cullen, O. Halevi and U. Oron. Low
level laser irradiation shows no histopathological
effect on myogenic satellite cells in tissue culture.
Laser Therapy 11:114-117.2001.
4. U. Oron, T. Yaakobi, A. Oron, G. Hayam, L. Gepstein,
T. Wolf, O. Rubin and S.A. Ben Haim. Attenuation of
the formation of scar tissue in rats and dogs post
myocardial infarction by low energy laser irradiation.
Lasers Surg. Med. 28: 204-211. 2001.
5. T. Wolf, L. Gepstein, U. Dror, G. Hayam, G. Uretzky,
U. Oron and S.A. Ben Haim. Detailed Endocardial mapping
accurately predicts the transmural extent of myocardial
infarction. J. Am. Coll. Cardiol. 37: 1590 - 1597.
2001.
6. N. Yaakov, S.A. Ben-Haim and U. Oron. Low power
laser irradiation reduces interstitial scarring in
isoproternol-induced hypertrophic rat heart. Laser
Therapy. Laser Therapy 11:190-197. 2001.
7. U. Oron. Regulation of skeletal muscle regeneration
and bone repair in vertebrates. MCZ Bulletin-Harvard
University.156: 297-303. 2001.
8. N. Ad and U. Oron. The impact of low energy laser
irradiation on infarct size in the rat following myocardial
infarction. Int. J. Cardiol. 80:109-116. 2001.
9. T. Yaakobi, Y. Shoshani, S. Levkovitz, O. Rubin,
S.A. Ben Haim and U. Oron. Long term effect of low
energy laser irradiation on infarction and reperfusion
injury in the rat heart. J. Appl. Physiol. 90: 2411-
2419. 2001.
10. G. Shefer, U. Oron, A. Irintchev, A. Wernig, and
O. Halevy. Skeletal muscle cell activation by low
energy laser irradiation: a role for the MAP/ERK pathway.
J. Cell Physiol. 187: 73-80. 2001.
11. N. Mirsky, Y. Krispel, Y. Shoshany, L. Maltz and
U. Oron. Promotion of angiogenesis by low energy laser
irradiation. Antioxidant. Redox Signa. 4: 785-790.
2002.
12. G. Shefer, T Partridge, L. Heslop, J.G. Gross,
U. Oron and O.Halevy. Low-energy laser irradiation
promotes the survival and cell - cycle of skeletal
muscle satellite cells. J.Cell Scienc.115: 1461-1469.
2002.
13. P. Sommer, U. Oron, E. Olavi Kajander and A. R.
Mester. Stressed cells survive better with light.
J. Proteome Res.1: 475-475. 2002.
14. A. P. Sommer, U. Oron, Anne-Marie Pretorius, D.S.
McKay, N. Ciftcioglu, A.R. Mester, E.O.Kajander and
H.T. Whelan. A preliminary Investigation into Light-Modulated
replication of nanobacteria and heart disease. J.
Clin.Laser Med Surg. 21: 231-235. 2003.
15. G. Shefer, I. Barash, U. Oron and O. Halevy. Low-energy
irradiation enhances de novo protein synthesis via
its effects on translation-regulatory proteins in
skeletal muscle myoblasts. Biocem. Biophys. Acta –
Mol. Cell Res.1593: 131-139.2003.
16. A.P. Sommer, Anne-Marie Pretorius, E. O. Kajander
and U. Oron. Biomineralization induced by stressed
nanobacteria. Crystal growth and Desig.4: 45-46. 2004.
17. A.P. Sommer, U. Oron, Anne-Marie Pretorius, D.S.
McKay, N. Ciftcioglu, A.R. Mester, E.O. Kajander and
H.T. Whelan. A preliminary Investigation into Light-Modulated
replication of nanobacteria and heart disease. J.
Clin. Laser Med. Surg. 21: 231-235. 2003.
18. A. P. Sommer, D.S. Mckay, N. Ciftcioglu, U. Oron,
A.R. Mester and E.O. Kajander. Living nanovesicles-chemical
and physical survival strategies of primordial biosystems.
J.Proteom. Res. 2: 441-443. 2003.
19. J. Streeter, L. De Taboada and U. Oron. Mechanisms
of action of light therapy for stroke and acute myocardial
infarction. Mitochondrion 4: 569-576. 2004.
20. A.P. Sommer, Anne-Marie Pretorius, E.O. Kajander
and U. Oron. Biomineralization induced by stressed
nanobacteria. Crystal Growth Desig. 4: 45-46. 2004.
21. A. Stein, D. Benayahu, L. Maltz and U. Oron. Low
level laser irradiation promotes proliferation and
differentiation of human osteoblasts in vitro. Photomed.
Laser Surg. 23: 161-166. 2005.
22. D. Fogel-Avni, S. Levkovitz, L. Maltz and U. Oron.
Protection of skeletal muscle from ischemia/reperfusion
injury by low energy laser irradiation. Photomed.
Laser Surg. 23: 273-277. 2005.
23. L. DeTaboada, S. Ilic, S. Leichliter, U. Oron,
A. Oron and J. Streeter. Transcranial application
of Low energy Laser Irradiation improves neurological
deficits in rats following acute stroke. Laser Surg.
Med. 2005. 38: 70-73.
24. U. Oron. Photoengineering of tissue repair in
skeletal and cardiac muscles - Review. Photomed. Laser
Surg. 24: 111-120. 2006.
25. H. Tuby, L. Maltz and U. Oron. Modulations of
VEGF and iNOS in the rat heart by low level laser
therapy are associated with cardioprotection and enhanced
angiogenesis. Laser Surg. Med. 2006. 38: 682-688.2006.
26. S. Ilic, S. Leichliter, J. Streeter, A. Oron,
L. DeTaboada, and U. Oron. Effects of Power Densities,
Continuous and Pulse Frequencies and Number of Sessions
of Low Level Laser Therapy on Intact Rat Brain. Photomed.
Laser Surg. 24: 458-466. 2006.
27. A. Oron, U. Oron, J. Chen, A. Eilam, C. Zhang,
M. Sadeh, Y. Lampl, J. Streeter, L. DeTaboada and
M.Chopp. Low level laser therapy applied transcranially
to rats following induction of stroke significantly
reduces long-term neurological deficits. Stroke. 37:2620-2624.
2006.
28. H. Tuby, L. Maltz and U. Oron. Low-level laser
irradiation (LLLI) promotes proliferation of mesenchymal
and cardiac stem cells in culture. Laser Surg. Med.39:
373-378. 2007.
29. Y. Lampl, J.A. Zivin, M. Fisher, R. Lew, L. Welin,B.
Dahlof, P. Borenstein, B. Andersson, J. Perez, C.
Caparo,S. Ilic and U. Oron. Infrared laser therapy
for ischemic stroke: a new treatment strategy: results
of the NeuroThera Effectiveness and Safety Trial-1
(NEST-1). Stroke. 38:1843-1849. 2007.
30. A. Oron, U. Oron, J. Sreeter, L. de Taboada, A.
Alexandrovich, V. Trembovier, E. Shoami. Low-level
laser therapy applied transcrnially to mice following
traumatic brain injury significantly reduces long-term
neurological deficits. J. Neurotrauma. 24: 651-656.
2007.
31. U. Oron, S. Ilic, L. Detaboada, J. Streeter. Ga-As
(808nm) Laser Irradiation enhances ATP production
in human neuronal cells in culture. Photomed. Laser
Surg. 25: 180-182. 2007.
32. G. Shefer, N. Ben-Dov, O. Halevy and U. Oron.
Primary myogenic cells see light: Improved Survival
of Transplanted Myogenic Cells following Low Energy
Laser Irradiation. Laser Surg. Med. 40: 38-45. 2008.
33. H.Tuby, L. Maltz and U. Oron. Implantation of
low-level laser irradiated mesenchymal stem cells
into the infarcted rat heart is associated with reduction
in infarct size and enhanced angiogenesis. Photomed.
Laser Surg. 27:227-233. 2009.
34. P.A.
Trimmer, K. M. Schwartz, M. K. Borland, L. De Taboada,
J. Streeter, and U. Oron. Reduced axonal transport
in Parkinson’s disease cybrid neurites is restored
by light therapy. Molecular Neurodegeneration. 4:26
.2009.
35. Oron U, Maltz L, Tuby H, Sorin V. and A. Czerniak.
Enhanced liver regeneration following acute hepatectomy
by low-level laser therapy. Photomed Laser Surg. 2010;
28(5):675-678.
36. H. Tuby, L. Maltz and U. Oron. Induction of autologous
mesenchymal stem cells in the bone marrow by low-level
laser therapy has profound beneficial effects on the
infarcted rat heart.Laser Surg. Med. In press.
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