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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.

Mester family
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 1967 study 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 reported:

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 pain
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-Beta 1
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.

Laser reactive oxygen
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.
 
Laser differentiation
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.

Bone volume
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 human stem cells
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.

Sources: Science Magazine, Harvard University [press release]



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Obligatory informative post
By geddarkstorm on 6/4/2014 9:58:43 PM , Rating: 3
It may be of interest that Oct4 and Nonog are two of the three or four (depending on the system) transcription factors used to turn any adult cell into an induced pluriopotent stem cell. Basically, in this case for dentin, the laser is making iPSC's or activating latent stem cell pools to proliferate (or both perhaps), which then go on to heal and regenerate the damage, rebuilding the tooth.

Implications? Huge.

Also suggests the acid method to induce iPSC production that was published not too long ago may have a similar mechanism, if that method even turns out to be reproducible and not bunk (there is some controversy surrounding that publication).

This really is a landmark study, and I am pleased to see the high resolution figures published here. They are fantastic and represent an absurd amount of work.

On another note, this may be yet another related reason why antioxidants beyond required levels do not improve health but instead are linked to increased all case mortality in meta studies of clinical and hospital data.




RE: Obligatory informative post
By abzillah on 6/5/2014 3:26:25 AM , Rating: 3
It is very interesting to see this. We study heat stress and light stress in plant species in our lab and we look at ROS and Heat Shot Proteins.
It seems like putting cells under a little stress may actually trigger machinery that protects it and heals it, but too much stress may kill the cells. This has been shown in our lab, where we put plants in 38 degrees Celsius for an hour before putting it in 45 degrees Celsius and this allows the plant to initiate machinery to protect the plant, and the plant is able to survive longer with this pre-treatment. With no pre-treatment and straight into 45 degrees Celsius, the plant dies within an hour, while with a pre-treatment it can survive up to 5 hours.


RE: Obligatory informative post
By Murloc on 6/5/2014 1:51:04 PM , Rating: 1
oh gosh we have to free those poor plants!
All life is worth the same!
Stop with your anthropocentric egoistical ways!


By geddarkstorm on 6/5/2014 8:29:18 PM , Rating: 2
So fascinating. Your research sounds great, and it would be really interesting of someone could do a comparative physiological investigation to see if there's a conserved mechanism or pathway of action between plants and animals. That could reveal a huge amount of important information, since plant cells are mostly totipotent while animal cells are mostly not. Where they overlap could give us the key to restoring our cells.


RE: Obligatory informative post
By MrBlastman on 6/5/2014 1:10:31 PM , Rating: 3
What I wonder is just exactly what in the laser is causing this. Is is the frequency of the beam or the modulation of a pulse? Or is it a combination of that and the polarized property of the energy delivery?

Perhaps we need to go further. Maybe it isn't just laser energy at all that can cause this. Perhaps multiple sorts of energy can create the same sort of stimulus at the suggested levels. What about low-level isotopes with a high rate of decay (due to them being on the verge of end-life or reduction to a point of non-effect to tissue rather than something severe. Perhaps with beta decay and a later injected encapsulent which would neutralize further reaction?

That is, if it isn't the property of light itself but raw energy being distributed to the sell as the effective agitant. But I'm not sure if this is the case from the article or not--or the study for that matter.

The reason I wonder is this ability to activate stem cells--alludes to a similar vein of research done with Rats that made headlines several weeks ago. If we can re-activate, or keep these things active in life that has allowed them to go dormant, the implications are stupendous.


By geddarkstorm on 6/5/2014 8:27:41 PM , Rating: 2
Very astute of you, MrBlastman!

http://www.ncbi.nlm.nih.gov/pubmed/21436606

Indeed, low levels of ionizing radiation (X-rays in this case) can stimulate mesenchymal stem cell proliferation (mesenchymal stem cells can repair things like muscle, heart, bone, and blood supplies).

It may also be a common pathway related to ROS production -- a response to a certain level of ROS above background but below cytolethal.

If that's the case, any energy source -- be it light, radiation, or chemical -- that can stimulate the proper amount of ROS production in cells and the activation of latent growth factors through that pathway, may stimulate regeneration of damage and even age related "wear and tear" (note, aging is basically related to the stem cells getting lazy, and anything that reactivates them can reverse aging until they go back to being lazy again, such as the "stitched together rats" experiment covered here awhile ago you allude to).

It's so fascinating. Laser light has an advantage over radio isotopes in that you can specify exactly where and when to apply it. On the other hand, radio isotopes have the advantage of a much longer lived stimulus that's non-invasive compared to laser light.

It does honestly seem like we are close to unraveling the mystery of aging and learning how to halt or reverse it to some degree (maybe not maximum life span, but definitely health span: i.e. be equivalent to your 20's till the day you suddenly drop).


What kind of light?
By Wombat_56 on 6/5/2014 7:18:10 PM , Rating: 2
There's no mention (in this article) of the wavelength of light used, only the power levels.

Also, does it have to be a laser? Would an LED or filtered conventional light source do as well?




RE: What kind of light?
By geddarkstorm on 6/5/2014 8:13:01 PM , Rating: 2
I haven't been able to get access to the article yet, but the laser was non-ionizing (lower than UV), and low power. Most likely it's an infrared laser (wavelength in the 900 nm and longer) as that penetrates living tissue while shorter wavelengths like visible light do not. Since they were shining this into the tooth, I doubt it was anything shorter than infrared, but can't say for sure without the paper.

Laser has an advantage as it can deliver more power in a coherent, local area for less energy cost than an LED array could do.


Therapeutic Low Level Laser therapy
By Jo Murphy on 6/5/2014 8:54:21 PM , Rating: 2
I have been using my LED (9 beads, 3 frequencies)and also a true laser (830nm x 30secs) for ten years at least. It is such a help in controlling inflammation and/or joint pain. Ideal for soft tissue pain like fibromyalgia. I don't need a licence, or a double blind clinical study, to tell me when my pain is reduced or eliminated (depending on the trauma). Huge help in healing bruises etc. Time to get all heads out of the sand and use these safe lasers to heal intractable wounds like lower leg ulcers. Seeing and feeling is believing! Look for Pekka Pointin's (Finland) work - and be reassured by a professional! Photosynthesis (generated by random light from the sun)is what generates plant energy (ATP), and therefore sustains life. Directed coherent light does the same for human tissue.
Jo M (NZ)




By Bubbacub on 6/6/2014 2:49:21 AM , Rating: 2
A tinfoil hat and a pair of dark glasses will successfully treat the non organic disease of 99% of people who are 'diagnosed' with fibromyalgia.

On topic - this study is very interesting. Need a well designed randomised clinical trial to see how it works against placebo treatment.


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