Promising laser advances

Dr. FinchUp-and-coming uses for lasers include treating scar contractures, addressing fibrotic disorders and enhancing photodynamic therapy (PDT) for certain skin cancers, says Justin Finch, M.D., director of the Center for Cutaneous Laser Surgery at the University of Connecticut Health Center in Mansfield. Dr. Finch spoke at the American Society for Laser and Medicine Surgery (ASLMS) annual conference held in April.

Releasing scar contractures

While cosmetic applications of lasers are well-established, they may hold more potential for other uses.

"For a long time we had very limited treatment options for patients with scar contracture," Dr. Finch said. These options often included costly surgical flap and graft procedures that are fraught with postsurgical morbidity, unpredictable efficacy and high recurrence rate.

"We've found that with a minimally invasive approach [to ablative fractional resurfacing (AFR)], many of these patients can achieve dramatic improvements in the range of motion of limbs affected by scar tissue," he said. These improvements can be so dramatic that AFR has become the standard of care in just 5 years.

"Scar contractures are particularly disabling when they cross a joint because they can cause the joint to contract and impair mobility," Dr. Finch said. Under the fibrous bands that form contractures erosion, non-healing wounds can occur and associated pain can impact patients' prognosis for prosthetic rehabilitation.

In the rehabilitation process ablative fractional laser treatment is not monotherapy. "It must be combined with intensive physical therapy as part of the rehabilitation process," he said. A well-documented case involved a 43-year-old Iraq war veteran who developed scar contracture of the left knee after being wounded by an improvised explosive device. Rather than surgical scar release and skin grafting, he underwent ablative fractional laser treatment. Three days later, his range of motion had increased 12 degrees and a persistent erosion healed. Two years after a second treatment, he had regained full range of motion.¹

If physicians can improve traumatic scars with ablative fractional lasers, said Dr. Finch, "It stands to reason that we could probably also improve other conditions that behave like scars. Among those is linear morphea, which is an automimmune-mediated process that results in spontaneous scar formation in the skin."

He presented a case involving a 27-year-old female runner who developed linear morphea across her left ankle, causing ankle flexion contracture that prevented her from running.

"She had been treated with every reasonable topical therapy, and phototherapy, without any improvement. After a single treatment with an ablative fractional CO₂ laser, her range of motion increased 5 degrees. A week later, she had a 20-degree increase," Dr. Finch said. Four months later she was able to resume running and other normal activities.²

"Following this proof of concept study, this technique is being applied on a broader basis," he said. In a recent case series, investigators enrolled 17 patients with plaque and linear morphea and randomly applied either 30 sessions of low-dose UVA-1 phototherapy or three sessions of fractional CO₂ laser to two comparably sized lesions on each patient. The fractional CO₂ laser provided a clear advantage, investigators write, and there were significant differences in clinical scores, collagen homogenization scores and patient satisfaction scores for the two treatments.³

Historically, before considering surgical intervention for scar contractures, physician would typically wait a year. “But with ablative fractional lasers, we think of intervening early, within the first 2 to 4 months," Dr. Finch said.

When treating scar contractures, "We try to approximate the depth of the ablative columns to penetrate through the full thickness of the scar. And we treat at low density ¾ typically less than or equal to 5 percent coverage," he said. Scars can improve with laser treatment alone, but patients typically have better outcomes if laser treatment is combined with medication, such as triamcinolone or 5-fluorouracil, both of which reportedly have similar efficacy. Triamcinolone may have more adverse effects than 5-fluorouracil, Dr. Finch said. Some observers have reported telangiectasia formation and increased scar width with triamcinolone treatment, which have not been reported with 5-fluorouracil.

For scar treatment, physicians tend to see results with between three and five treatments, but “that's something we're learning as we go," he said.

AFR gently lengthens the contractures. "We still don't know exactly how it works. Part of the lengthening happens almost immediately or within days after a scar treatment," probably due to fenestration created by multiple microscopic holes. Some microscopic studies show a shift in collagen profile in treated scars from the very inflexible collagen I, to the more flexible collagen III. As researchers learn more about this multifactorial process, “We will learn how better to apply these treatments and select patients for treatment," he said.

Next: Pumping up PDT

Pumping up PDT

As skin cancer grows increasingly more prevalent, "Finding ways to utilize lasers to enhance drug delivery for preventing and treating skin cancers becomes more important," Dr. Finch said.

Many studies have shown benefits from using lasers to enhance PDT for skin cancers. "The recurrence rates are still high enough that it's not a first-line treatment. But for patients with multiple tumors or genetic syndromes who are unable to tolerate surgery, it's another tool we can use to improve outcomes," he said.

A head-to-head prospective, randomized, blinded study compared two sessions of traditional PDT including methyl aminolevulinate (MAL) versus one session performed after fractional ablation with an erbium:YAG laser for nodular basal cell carcinoma. Three months later, 50% of patients in the traditional PDT group had complete responses, versus 84% in the laser-assisted PDT group (p = 0.026).⁴ The corresponding figures at one year were 22% and 80%. "An 80% response rate is not enough for laser-assisted PDT to be a first-line treatment, but it certainly can be considered second- or third-line in appropriate populations. Recurrence rates at one year were 6.3% for AFR-PDT and 55.6% for MAL-PDT (p = 0.006).

Penetration of the stratum corneum is the rate-limiting step in absorption of topical treatments including photosensitizers. A recent study showed that AFR outperformed microdermabrasion, microneedling and nonablative lasers for laser-assisted drug delivery to the skin.⁵

"That's probably because fractionated lasers vaporize the skin, creating a potential space into which you can deposit a reservoir" from which the drug slowly disperses, Dr. Finch said. "The zone of coagulation around each microscopic ablative column impairs the systemic absorption of the drug. This study showed what we all expected:  Ablative fractional lasers provide the best pretreatment, at least for aminolevulinic acid (ALA), and probably most drugs," he said.

Because AFR drug delivery remains a relatively new field, "We're still working out how much of a fraction of the skin we want to treat. How deep do we want to go? How much coagulation do we want to use? A couple years ago, we didn't know the answers to those questions," he said.

Now researchers are finding that a density around 100 channels per cm,² or approximately 5% or less of the skin surface area, with a depth of around 200 µm appears to work best. "Very high densities wipe out dermal vasculature, decreasing drug absorption," he said. Lasers that provide the most coagulation, such as CO₂ lasers, provide optimal skin absorption, while less coagulative lasers such as the erbium:YAG encourage systemic absorption.

PDT advances not withstanding,  the most fascinating, cutting-edge applications of laser-assisted drug delivery involve delivering living tissue through the skin. In a pilot study, investigators used laser-assisted delivery of stem cells to create a functionally chimeric mouse.

First, they applied radiation to immunosuppressed mice to ablate their bone marrow. "Then they treated the skin with an ablative fractional laser and topically delivered the donor stem cells to the surface of the skin. It's a very elegant study which demonstrated that three weeks after a single treatment, the donor cells had not only engrafted, but also had functionally recovered in far-ranging tissues such as the marrow and spleen,^6,7" he said. "This technique has never been performed in a human. But one could envision an era when we can perform such transplants via an elegantly simple skin procedure."

In another study, investigators treated the skin of mice with fractional erbium:YAG laser to deliver a lysozyme antigen as a vaccine. "They chose that antigen because it's an enormous 129 amino acid molecule that can't easily traverse the stratum corneum." Any post-treatment effects could only be explained by systemic absorption of the vaccine by its permeating through the ablative laser columns. "In the mice treated with the fractionated laser protocol prior to delivery of the lysozyme antigen, production of peripheral antibodies in the serum increased threefold,⁸" he said.

In both mouse studies, researchers did not merely want to deliver treatment to the skin, but they wanted to deliver treatment through the skin so it would be absorbed systemically. "In such cases, the erbium:YAG laser is probably a better choice than CO₂ because it doesn't cause that zone of thermal coagulation," Dr. Finch said.

Disclosures: Dr. Finch reports no financial conflicts of interest related to this topic.

References

1.  Shumaker PR, Kwan JM, Landers JT, Uebelhoer NS. Functional improvements in traumatic scars and scar contractures using an ablative fractional laser protocol.J Trauma Acute selection of the two fuzzy Care Surg. 2012;73(2 Suppl 1):S116-21.

2. Kineston D, Kwan JM, Uebelhoer NS, Shumaker PR. Use of a fractional ablative 10.6-μm carbon dioxide laser in the treatment of a morphea-related contracture. Arch Dermatol. 2011;147(10):1148-50.

3. Shalaby SM, Bosseila M, Fawzy MM, Abdel Halim DM, Sayed SS, Allam RS. Fractional carbon dioxide laser versus low-dose UVA-1 phototherapy for treatment of localized scleroderma: a clinical and immunohistochemical randomized controlled study. Lasers Med Sci. 2016;31(8):1707-1715.

4. Choi SH, Kim KH, Song KH. Er:YAG ablative fractional laser-primed photodynamic therapy with methyl aminolevulinate as an alternative treatment option for patients with thin nodular basal cell carcinoma: 12-month follow-up results of a randomized, prospective, comparative trial.J Eur Acad Dermatol Venereol. 2016;30(5):783-8.

5. Bay C, Lerche CM, Ferrick B, Philipsen PA, Togsverd-Bo K, Haedersdal M. Comparison of physical pretreatment regimens to enhance protoporphyrin IX Uptake in photodynamic therapy: a randomized clinical trial. JAMA Dermatol. 2017;153(4):270-278.

6. Waibel J, Davis S, Badiavas E. A pilot study of laser assisted delivery of allogenic mesenchymal cutaneous stem cells resulting in functional chimeric mouse model. Laser Surg Med. 2012;44(Suppl 24):1-94.

7. Rodriguez-Menocal L, Salgado M, Davis S, et al. Percutaneous bone marrow transplantation using fractional ablative erbium:YAG laser. PLoS One. 2014;9(3):e93004.

8. Lee WR, Pan TL, Wang PW, Zhuo RZ, Huang CM, Fang JY. Erbium:YAG laser enhances transdermal peptide delivery and skin vaccination.J Control Release. 2008;128(3):200-8