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Microneedle pretreatment shortened ALA incubation time

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Microneedles poised to become increasingly valuable clinically

The effectiveness of photodynamic therapy (PDT) as a field therapy option for actinic keratoses (AKs) has been well documented. However, treatment is limited by poor or variable transepidermal absorption owing to the hydrophilic nature of aminolevulinic acid (ALA).

To overcome the problem of transepidermal delivery, patients wait for hours at a time between ALA application and the light treatment. These prolonged incubation times limit usefulness. Petukhova et al. hypothesized that microneedles would enhance penetration and decrease incubation period without compromising safety and efficacy. The results suggest that an effective and safe PDT treatment can be achieved by using microneedles as means to expedite drug penetration. These results also suggest that further reduction of incubation time will not be achieved by better transepidermal penetration.

As envisioned in 1971, microneedles can have an important clinical role and can be an important tool in the dermatologist’s armamentarium. Microneedles are painless when compared with hypodermic needles, do not require specific training, minimize risk of needlestick injuries, can potentially reduce cost, and improve patient compliance and access. Therefore, microneedle-based devices can potentially be used at home by patients in a safe manner. Mostly in preclinical trials, as well as in some clinical trials, microneedles have been successfully used to deliver various drugs and vaccines.

Importantly, dermatologists are uniquely positioned to research this novel drug delivery method because they routinely treat cutaneous disease. This can be leveraged by dermatologists to use microneedles not only for dermal rejuvenation purposes but also to enhance drug delivery for dermatological indications. Therefore, the study by Petukhova et al. not only provides practical information for treatment of AKs with PDT but can also be viewed as a call for action to all dermatologists to lead innovation in the field and revolutionize dermatological drug delivery.

These comments are adapted from an accompanying editorial by Hadar Lev-Tov, MD, of the University of Florida, Miami. He reported having no disclosures.


Pretreatment with microneedles provided a faster, less painful, way to treat facial actinic keratoses (AKs) with photodynamic therapy, with similar clearance rates as would be expected with traditional therapy, in a study of 33 patients.

This approach reduced the incubation time of aminolevulinic acid (ALA) to 20 minutes, with comparable results to one-hour ALA incubation times. “Interestingly, the secondary outcome of pain associated with blue light exposure during photodynamic therapy was nominal and not significantly different from the sham side,” reported Tatyana A. Petukhova, MD, and her associates in the department of dermatology at the University of California, Davis (JAMA Dermatol. 2017 May 17. doi: 10.1001/jamadermatol.2017.0849).

“Pain associated with PDT is the most severe adverse effect and may lead to interruption or discontinuation of treatment, resulting in refusal to repeat the process at a future date owing to unbearable discomfort,” they wrote. Patients also reported little to no swelling or pain after treatment and minimal erythema and peeling.

The randomized, split-face, single-blinded controlled trial enrolled 33 patients, with at least eight AKs on their faces, from a university dermatology outpatient clinic from 2015 to 2016. They were randomized to receive either 10 minutes or 20 minutes incubation time with ALA, and 32 completed the study. Those in the 20-minute group had a mean of 25 grade II facial AKs, and those in the 10-minute group had an average of 31 grade II facial AKs.

Before administration of ALA, each patient received pretreatment with a microneedle roller on one side of their face and a sham roller on the other side. On each half of their faces, the microneedle device (a single-use sterile array of microneedles measuring 200 mcm) or sham roller was rolled forward and backward eight times in four directions.

They were exposed to blue light for 1,000 seconds at an average wavelength of 478 nm, an overall fluence of 10 J/cm2, and advised to avoid sun exposure for 36 hours after treatment.

At follow-up one month later, among the patients with a 20-minute ALA incubation time, the mean AK clearance rate was 76% on the side with microneedle pretreatment, compared with 58% on the sham side (P less than .01). This included three patients with complete clearance. The efficacy of microneedle pretreatment with a 20-minute incubation time is similar to that of 1-hour incubation times with ALA. PDT typically uses 1-4 hours of incubation time.

Among the patients who received a 10-minute ALA incubation time, a mean of 43% of AKs on the microneedle side and 38% on the sham side cleared, a difference that was not statistically significant. Participants did not rate the pain as significantly different between each side of their face and both groups reported low levels of pain overall.

One limitation of the study was the short follow-up time. “Because actinic damage is cumulative, there is potential for thicker AKs to recur or for new lesions to develop during a longer follow-up period,” the authors noted.

The research was partly funded by an author’s University of California, Davis, Medical Student Research Fellowship. The authors reported having no disclosures.

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