Study Silences Controversy, Illuminates the Biochemistry of Laser Healing
June 4, 2014 9:36 PM
Study shows that both in live rodents and culture human cells, lasers can trigger healing from dental surgery
Lasers -- which derive their name from the acronym for "light amplification by stimulated emission of radiation" -- have been a hot field of study ever since it was invented around 1957 by Bell Labs researchers Charles Hard Townes and Arthur Leonard Schawlow, and Columbia University, graduate student Gordon Gould. Many medical applications -- ranging from LASIK eye surgery to bloodless surgery -- have focused on high power lasers.
I. Low-Level Laser Therapy (LLLT): Science or Fraud?
But low-power lasers -- best known today for their applications in consumer electronics, such as CD, DVD, and Blu-Ray disc drives -- have long been suggested to hold medical promise, as well. For the last few decades the concept has received spurts of attention, but remains controversial, with little ongoing work dedicated to it.
To understand why this is, you have to venture back to the work of
Dr. Endre Mester
-- the father of the proposed treatment. A native of Hungary, Dr. Mester did most of his work during an era in which Hungary was a communist satellite state of the Soviet Union.
Dr. Mester is believed to have been only the fourth physician globally to have embarked on laser medical studies of any kind, and was the first to publish results suggesting low-powered lasers could stimulate cell growth or healing. This work began in 1965, and would continue into the late 1970s at his Laser Research Center in Semmelweis, Hungary, which he founded in 1974.
Dr. Endre Mester (center) is pictured with his sons, Dr. Andrew Mester and Dr. Adam Mester. The elder doctor is known as the father of low-level laser therapy. [Image Source: Laser.nu]
In a seminal
he reported that shaved mice regrew their back hair faster when exposed to treatments from a low light laser.
Recapping his pioneering work in the 1960s and 1970s, Dr. Endre Mester, along with his sons, Dr. Adam Mester and Dr. Andrew Mester, in 1985 wrote a review of various observed therapeutic effects of low power lasers. In the paper they
Low-energy laser radiation was found to have a stimulating effect on cells, and high-energy radiation had an inhibiting effect. The application of lasers to stimulate wound healing in cases of nonhealing ulcers is recommended.
In the Western research community, these assertions for decades were viewed with skepticism. Part of the skepticism may have been due to biases. During the Cold War, there was a widely documented disdain and skepticism in the American academic community for research done in the Soviet Union and its satellite states. To make matters worse, one of the major applications Dr. Mester suggested for his work was in pain treatment -- a field fraught with snake oil cures. These factors inevitably created skepticism over whether the technique was even worth investigating.
Laser therapy has been proposed as a treatment for chronic pain and inflammation, as well as to promote healing or hair growth. However, some have argued that there was little evidence to explain such affects and the therapies might be fraudulent. [Image Source: Rebecca Marsh]
But over the past few decades some researchers in Western Europe and the U.S. did investigate the topic sporadically. That leads in turn to the more scientifically important reason why this seemingly terrific therapy was never taken seriously -- it was very difficult to understand and rigorously study. One difficulty was that the effects were subtle, failing to provide a clear picture of so called "photobiomodulation" -- that the light was somehow triggering novel, positive biochemical activity. A second difficulty associated with pain therapy, which is a field often associated with fraudulent medical claims.
II. Let There be Light
That's precisely why
a new paper published
in the prestigious peer-reviewed journal
Science Translation Medicine
is so important. The study was performed by a team of researchers at Harvard University's Engineering, Medical, and Dental schools.
The paper offers one of the most conclusive and careful control set experiments whose results show clear evidence of photobiomodulation in rats. But what makes the paper truly groundbreaking is that it offers, for the first time, a hypothesis regarding a mechanism by which photobiomodulation may occur in mammals.
The paper's terrifically thorough presentation is hardly accidental. The first author was
Praveen, R. Arany
, a staff researcher who holds a Ph.D in health sciences from Harvard and multiple other advanced degrees in clinical research (B.D.S., M.D.S., M.M.Sc). The study's senior author was
Professor David J. Mooney
, a Harvard Bioengineering core faculty member who is known as one of the nation's top tissue engineering researchers and stem cell experts. In total, 12 other top MDs, Ph.Ds, and graduate students at Harvard and related medical facilities also participated in the work.
The study's story begins with an investigation into using lasers to speed healing in rats that have undergone dental surgery. During the surgical procedure enamel -- the hard, white,
bony mineral cap of the tooth
-- was penetrated by a drill. The drill damaged the dentin, the living bony matrix that composes the large portion of rodent and human teeth, by volume. Following the so-called "pulp-capping procedure" -- similar to a human cavity filling procedure -- researchers treated the injured dentin with low-powered laser light.
TGF-β1 is a key regulator of stem cell differentiation. [Image Source: Wikimedia Commons]
The researchers found that the laser light produced reactive oxygen species (ROS), including the highly reactive "superoxide" compound. These species in turn modified a methionine residue of latent TGF-β1 (LTGF-β1),
a factor associated with bone growth and stem cell differentiation
. The activated factor was then able to activate genes such as Oct4 and Nonog, which transformed local cells into stem cells and or triggered local stem cell populations to differentiate into odontoblasts, which rebuilt the damaged dentin matrix.
Higher levels of activating reactive oxygen species were detected in laser-treated mice.
[Image Source: Science/AAAS]
A mid-level laser capable of delivering 3 J/cm^2 (on the high end of "low-level" lasers) produced the best result. Two other laser intensities -- 0.03 J/cm^2 and 0.3 J/cm^2 were also tested. Even at 0.03 J/cm^2 the rats showed impressive, albeit lesser, gains. The best results were seen after therapy sessions of an hour, but therapy sessions of 15 minutes were seen in Western Blot studies to produce LTGF-β1.
The laser appeared to clearly trigger differntiation in rodents and human cells. [Image Source: Science/AAAS]
Researchers observed that the laser-treated rats had more bone deposition sites and had a higher, bone volume to tooth volume (BV/TV) ratio, indicating improved healing.
The drilled teeth (top left) showed increased bone volume (top right) when exposed to laser therapy. [Image Source: Science/AAAS]
Perhaps the most exciting part of the work is that after all these terrific in-vivo results, researchers tested LLLT on recombinant human latent TGF-β1 (rhLTGF-β1) (the human equivalent of the pivotal mouse gene, with the recombinant part meaning it was inserted into a separate organism via gene therapy). The human gene appeared to undergo photobiomodulation via the same route -- reactive oxygen species -- as its rodent equivalent.
Laser treated human cells express actin (green stain, upper left) indicating they're becoming bone-growing cells. [Image Source: AAAS/Science]
Last, but not least, the researchers tested the method on actual cultures of human dental stem cells (hDSC) and showed the laser therapy enhanced the rate of differentiation into odontoblasts. The researchers confirmed this enhancement by using immunofluorescent microscopy and staining to note the formation of an actin cytoskeleton, which serves as a dentin deposition matrix. The
formation of this skeleton
indicates that the hDSCs has differentiated into or is in the process of differentiating into odontoblasts.
The study is very compelling and appears to show that it is highly probably that laser light treatments will help patients heal from dental surgeries. The only thing left to do, at this point is to conduct clinical trials to test that hypothesis, now that the mechanism is likely understood.
The study also raises many other questions such as how ROS and other side effects of laser therapy play a role in treating pain, a key therapeutic usage that has been anecdotally suggested, but not rigorously studied in animal models.
Harvard University [press release]
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