By Deborah Borfitz
June 11, 2019 | Laboratory groups the world over have applied a multiphoton laser microscope directly to the skin to peer at living tissue using a beam of light. But University of British Columbia (UBC) researchers are the first to demonstrate that the same instrument can also treat tissue simply by turning up the power of the laser, says Harvey Lui, professor at the department of dermatology and skin science at UBC and the Vancouver Coastal Health Research Institute, and a dermatologist at BC Cancer.
Lui is co-author of a study recently published in Science Advances (DOI: 10.1126/sciadv.aan9388) that proved the principle. UBC researchers successfully used a homemade multi-photon laser microscope to not only image blood vessels in the skin but also to target single blood vessels and precisely close them off or reroute blood flow.
The novel technique could be applied to any potential target within the tissue that can be reached by light, including clusters of cells or microorganisms, with no cutting or staining required, says Lui. "We're actually using the biochemical properties of the skin itself… to visualize the structures we're interest in."
If the device can be miniaturized—something UBC clinicians and engineers are already collaboratively working on—it could be sent down an endoscope, Lui says. That raised the possibility of gastroenterologists using the tiny microscope in the colon or esophagus, pulmonologists in the lungs, and urologists in the bladder to diagnose localized malignancies and treat them on the spot microscopically. It may be particularly useful in treating early-stage cancers and determining the margins, he adds.
Even in the brain and eyes, where precision is paramount, the microscope might have applications, says Lui. He is especially optimistic about its ability to improve surgical treatment of diabetic retinopathy, when "a fraction of a millimeter can mean the difference between blindness and curing an abnormal blood vessel."
This is not a radical idea in dermatology, where physicians are often both diagnostician and treating physician, says Lui. Dermatologists frequently perform micrographic surgery on skin cancer patients right in their office. But using the newly developed microscope, they might one day be able to avoid the step of having to process tissue externally to guide treatment progress.
Making the Magic Happen
The instrument, in its current form, is a "little bit cumbersome" but also not designed to be used in the clinic or operating room, says Lui. The specialized microscope, custom-built for the skin, sits on a table with the probe attached to an articulated arm and is roughly the size of a large hairdryer. The plan is to create a handheld version with the help of UBC mechanical and electrical engineers to make the technology practical in real-world care settings.
The multiphoton effect is what gives the device precision and depth of penetration and "allows the magic to happen," says Lui. In medicine, lasers are typically used in single-photon mode where light energy gets absorbed only if it arrives at precisely the wavelength that a molecule can accept.
With multiple photons, the light energy of individual photons arriving at the molecule at the same time collectively provide the exact energy needed, he explains. Smaller photons in the mix can penetrate tissue more deeply but still pack the punch of the larger energy photons. But the only way to achieve this multiphoton effect is to use an ultra-fast laser producing a pulse of light every quadrillionth (a millionth of a billionth) of a second, he says.
Research with the microscope has involved both mice and man—Lui himself volunteered for a related study that is examining the skin's microscopic reactions to ultraviolet light exposure over time. Ultraviolet light causes most skin cancers, but scientists don't know what cells are absorbing it or exactly how they're being altered, he says. Preliminary studies are now underway with skin cancer patients, and the research team will be exploring other organ systems where the microscope could have clinical value.
Study sponsors include the Canadian Institutes of Health Research (equivalent to the National Institutes of Health in the US), Canadian Dermatology Foundation, VGH & UBC Hospital Foundation and the BC Hydro Employees Community Services Fund, says Lui. His main collaborator is Haishan Zeng, senior author of the Science Advances study and a professor in the department of dermatology and skin science at UBC and BC Cancer. Zeng is a biophysicist and world expert on the interaction of light with the skin, Lui notes.
Beyond Disease Treatment
The path to commercialization will be determined by consultations with regulators at the FDA and Health Canada, Lui says. If currently marketed, but less precise, laser devices that treat blood vessels in the skin are deemed predecessor devices, the microscope may be able to take the less stringent marketing pathway, which in the U.S. is the 510(k) premarket notification process.
It may well be the microscope will prove useful as a research tool to better understand certain diseases—for example, an ischemic stroke model for basic biology studies, says Lui. It is known that the main cause of stroke is blocked blood flow in the brain, but not the exact reactions that are happening. "Maybe we can use the device to precisely cut off or close off certain blood vessels in the brain and observe those effects, and by doing that better understand the effects of stroke or how to rescue brain tissue."