Novel 40 µm spot size 3050/3200 nm DFG laser versus CO2 laser for laser-assisted drug delivery.

BACKGROUND AND OBJECTIVES: The use of ablative fractional lasers to enhance the delivery of topical drugs through the skin is known as laser-assisted drug delivery. Here, we compare a novel 3050/3200 nm difference frequency generation (DFG) fiber laser (spot size: 40 µm) to a commercially used CO2 laser (spot size: 120 µm). The objective is to determine whether differences in spot size and coagulation zone (CZ) thickness influence drug uptake. MATERIALS AND METHODS: Fractional ablation was performed on ex-vivo human abdominal skin with the DFG (5 mJ) and CO2 (12 mJ) lasers to generate 680 µm deep lesions. To evaluate drug delivery, 30 kDa encapsulated fluorescent dye was topically applied to the skin and histologically analyzed at skin depths of 100, 140, 200, 400, and 600 µm. Additionally, transcutaneous permeation of encapsulated and 350 Da nonencapsulated dye was assessed using Franz Cells. RESULTS: The DFG laser generated smaller channels (diameter: 56.5 µm) with thinner CZs (thickness: 22.4 µm) than the CO2 laser (diameter: 75.9 µm, thickness: 66.8 µm). The DFG laser treated group exhibited significantly higher encapsulated dye total fluorescence intensities after 3 h compared to the CO2 laser treated group across all skin depths (p < 0.001). Permeation of nonencapsulated dye was also higher in the DFG laser treated group vs the CO2 laser treated group after 48 h (p < 0.0001), while encapsulated dye was not detected in any group. CONCLUSION: The DFG laser treated skin exhibited significantly higher total fluorescence uptake compared to the CO2 laser. Additionally, the smaller spot size and thinner CZ of the DFG laser could result in faster wound healing and reduced adverse effects while delivering similar or greater amount of topically applied drugs.

Assessment of a 3050/3200 nm fiber laser system for ablative fractional laser treatments in dermatology.

BACKGROUND AND OBJECTIVES: Mid-infrared (IR) ablative fractional laser treatments are highly efficacious for improving the appearance of a variety of dermatological conditions such as photo-aged skin. However, articulated arms are necessary to transmit the mid-IR light to the skin, which restricts practicality and clinical use. Here, we have assessed and characterized a novel fiber laser-pumped difference frequency generation (DFG) system that generates ablative fractional lesions and compared it to clinically and commercially available thulium fiber, Erbium:YAG (Er:YAG), and CO2 lasers. MATERIALS AND METHODS: An investigational 20 W, 3050/3200 nm fiber laser pumped DFG system with a focused spot size of 91 µm was used to generate microscopic ablation arrays in ex vivo human skin. Several pulse energies (10-70 mJ) and pulse durations (2-14 ms) were applied and lesion dimensions were assessed histologically using nitro-blue tetrazolium chloride stain. Ablation depths and coagulative thermal damage zones were analyzed across three additional laser systems. RESULTS: The investigational DFG system-generated deep (>2 mm depth) and narrow (<100 µm diameter) ablative lesions surrounded by thermal coagulative zones of at least 20 µm thickness compared to 13, 40, and 320 µm by the Er:YAG, CO2 , and Thulium laser, respectively. CONCLUSION: The DFG system is a small footprint device that offers a flexible fiber delivery system for ablative fractional laser treatments, thereby overcoming the requirement of an articulated arm in current commercially available ablative lasers. The depth and width of the ablated microcolumns and the extent of surrounding coagulation can be controlled; this concept can be used to design new treatment procedures for specific indications. Clinical improvements and safety are not the subject of this study and need to be explored with in vivo clinical studies.

Ultrasonic delivery of silica-gold nanoshells for photothermolysis of sebaceous glands in humans: Nanotechnology from the bench to clinic.

Recent advances in nanotechnology have provided numerous opportunities to transform medical therapies for the treatment of diseases including cancer, atherosclerosis, and thrombosis. Here, we report, through in vitro studies and in vivo human pilot clinical studies, the use of inert, inorganic silica-gold nanoshells for the treatment of a widely prevalent and researched, yet poorly treated disease of acne. We use ~150nm silica-gold nanoshells, tuned to absorb near-IR light and near-IR laser irradiation to thermally disrupt overactive sebaceous glands in the skin which define the etiology of acne-related problems. Low-frequency ultrasound was used to facilitate deep glandular penetration of the nanoshells. Upon delivery of the nanoshells into the follicles and glands, followed by wiping of superficial nanoshells from skin surface and exposure of skin to near-infrared laser, nanoshells localized in the follicles absorb light, get heated, and induce focal thermolysis of sebaceous glands. Pilot human clinical studies confirmed the efficacy of ultrasonically-delivered silica-gold nanoshells in inducing photothermal disruption of sebaceous glands without damaging collateral skin.

Acne Treatment Based on Selective Photothermolysis of Sebaceous Follicles with Topically Delivered Light-Absorbing Gold Microparticles.

The pathophysiology of acne vulgaris depends on active sebaceous glands, implying that selective destruction of sebaceous glands could be an effective treatment. We hypothesized that light-absorbing microparticles could be delivered into sebaceous glands, enabling local injury by optical pulses. A suspension of topically applied gold-coated silica microparticles exhibiting plasmon resonance with strong absorption at 800 nm was delivered into human pre-auricular and swine sebaceous glands in vivo, using mechanical vibration. After exposure to 10-50 J cm(-2), 30 milliseconds, 800 nm diode laser pulses, microscopy revealed preferential thermal injury to sebaceous follicles and glands, consistent with predictions from a computational model. Inflammation was mild; gold particles were not retained in swine skin 1 month after treatment, and uptake in other organs was negligible. Two independent prospective randomized controlled clinical trials were performed for treatment of moderate-to-severe facial acne, using unblinded and blinded assessments of disease severity. Each trial showed clinically and statistically significant improvement of inflammatory acne following three treatments given 1-2 weeks apart. In Trial 2, inflammatory lesions were significantly reduced at 12 weeks (P=0.015) and 16 weeks (P=0.04) compared with sham treatments. Optical microparticles enable selective photothermolysis of sebaceous glands. This appears to be a well-tolerated, effective treatment for acne vulgaris.

Subsurface skin renewal by treatment with a 1450-nm laser in combination with dynamic cooling.

A new nonablative laser device, Smoothbeam, has been under evaluation for nonablative wrinkle reduction in skin with minimal side effects. This device incorporates a laser at 1450-nm wavelength to heat the dermis and cryogen spray cooling to prevent epidermal damage. The thermal injury created is internal and imperceptible. The wound-healing response to this internal injury causes improvement in the appearance of skin wrinkles. Biopsies taken immediately after treatment showed mild residual thermal damage (RTD) at a depth range of 150 to 400 microm, which is the dermal zone where most solar elastosis resides. Biopsies from two months after treatment showed fibroplasia extending over a range of depths similar to the acute RTD zones. An improvement in wrinkle severity was noted on the treated side compared with the control side.

Temporally and spectrally resolved fluorescence spectroscopy for the detection of high grade dysplasia in Barrett's esophagus.

BACKGROUND AND OBJECTIVES: Temporal and spectral fluorescence spectroscopy can identify adenomatous colonic polyps accurately. In this study, these techniques were examined as a potential means of improving the surveillance of high grade dysplasia (HGD) in Barrett's esophagus (BE). STUDY DESIGN/MATERIALS AND METHODS: Using excitation wavelengths of 337 and 400 nm, 148 fluorescence spectra, and 108 transient decay profiles (at 550 +/- 20 nm) were obtained endoscopically in 37 patients. Corresponding biopsies were collected and classified as carcinoma, HGD, or low risk tissue (LRT) [non-dysplastic BE, indefinite for dysplasia (IFD), and low grade dysplasia (LGD)]. Diagnostic algorithms were developed retrospectively using linear discriminant analysis (LDA) to separate LRT from HGD. RESULTS: LDA produced diagnostic algorithms based solely on spectral data. Moderate levels of sensitivity (Se) and specificity (Sp) were obtained for both 337 nm (Se = 74%, Sp = 67%) and 400 nm (Se = 74%, Sp = 85%) excitation. CONCLUSIONS: In the diagnosis of HGD in BE, steady-state fluorescence was more effective than time-resolved data, and excitation at 400 nm excitation was more effective than 337 nm. While fluorescence-targeted biopsy is approaching clinical usefulness, increased sensitivity to dysplastic changes-possibly through modification of system parameters-is needed to improve accuracy levels.

Acne treatment with a 1,450 nm wavelength laser and cryogen spray cooling.

BACKGROUND AND OBJECTIVES: A laser with a wavelength in the mid-IR range targeting the depth in skin where sebaceous glands are located in combination with cryogen spray cooling was evaluated for treatment of acne. In this non-ablative treatment, the laser energy heats the dermal volume encompassing sebaceous glands whereas the cold cryogen spray preserves the epidermis from thermal damage. STUDY DESIGN/MATERIALS AND METHODS: Monte Carlo simulations and heat transfer calculations were performed to optimize the heating and cooling parameters. A variety of heating and cooling parameters were tested in an in vivo rabbit ear study to evaluate the histological effect of the device on sebaceous glands and skin. Similar experiments were performed on ex vivo human skin. A clinical study for the treatment of acne on backs of human males was also conducted. RESULTS: Monte Carlo simulations and heat transfer calculations resulted in a thermal damage profile that showed epidermal preservation and peak damage in the upper dermis where sebaceous glands are located. Ex vivo human skin histology confirmed the damage profile qualitatively. In vivo rabbit ear histology studies indicated short-term thermal alteration of sebaceous glands with epidermal preservation. In the human clinical study on the back, a statistically significant reduction in lesion count on the treated side compared to the control side was seen (p < 0.001). Side effects were transient and few. CONCLUSIONS: The studies reported here demonstrate the feasibility of treating acne using a photothermal approach with a mid-IR laser and cryogen cooling.

Non-ablative cutaneous remodeling with a 1.45 microm mid-infrared diode laser: phase I.

BACKGROUND: Presented here is phase I of a three-part study of non-ablative cutaneous remodeling with a 1.45 microm diode laser configured with a cryogen spray cooling device. METHODS: Eight men and two women (average age of 67 years) with Fitzpatrick skin phototypes I-IV were treated at postauricular sites. Treatment consisted of one or two passes with a 4mm spot and an average power of 12 W. Heating times ranged from 150 ms to 500 ms applied over two to six treatment cycles. One treatment 'cycle' lasted for 100 ms and consisted of programmable parallel cryogen spray cooling pulses interspersed with unopposed heating. Biopsies were obtained at baseline, immediately after treatment, and at 2 months. RESULTS: Patients were assessed 1 day, 1 week, 1 month and 2 months after treatment. Treatments were well tolerated with minimal pain, with a trend towards increasing discomfort with longer heating times. Erythema and edema were also mild and short-lived. There was a direct relationship between the degree of erythema and edema, and longer unopposed heating times. Mild hyperpigmentation occurred at only three treatment sites. Epidermal burns usually presented as immediate whitening in 11 of 60 one-pass sites and four of 16 two-pass sites. Whitening was associated with longer unopposed heating times. Atrophic, pitted scars occurred at two single-pass sites and three double-pass sites. Baseline biopsies demonstrated solar elastosis in a 375 microm thick band (mean range from 100 microm to 480 microm deep in the dermis). Immediate post-treatment biopsies demonstrated thermal damage in a 333 microm thick band (mean range from 311 microm to 644 microm deep in the dermis). Finally, dermal fibrosis was observed 2 months after treatment in a 272 microm thick band (mean range from 148 microm to 420 microm deep in the dermis). CONCLUSION: The 1.45 microm diode laser is capable of targeting dermal collagen and stimulating fibrosis at depths where solar elastosis resides. Longer unopposed heating times corresponded to increased erythema, edema, and pain, which were typically mild and short-lived. Epidermal burns can result in pitted scars.

Non-ablative cutaneous remodeling with a 1.45 microm mid-infrared diode laser: phase II.

BACKGROUND: Presented here is phase II of a three-part study of non-ablative cutaneous remodeling with a 1.45 microm diode laser configured with cryogen spray cooling. In phase I, safe heating and cooling parameters were established by examining gross and microscopic changes induced by the laser. Phase II examines clinical changes and side effects in the treatment of single facial rhytids. METHODS: Two men and seven women with Fitzpatrick skin phototypes I-III were treated. Single facial rhytids were treated on three separate occasions 3 weeks apart (six periorbital and three perioral). Single, control wrinkles on the contralateral sides were treated with cryogen spray cooling alone. Subjects were treated with single passes with a 5mm spot for the first two treatments. Owing to a modification in the handpiece design, a 4mm spot was used for the third and final treatment. The average power was 12 W. At each treatment visit, heating times ranged from 200 ms to 300 ms, applied as a series of heating/cooling cycles. One treatment 'cycle' lasted for 100 ms and consisted of continuous laser heating interspersed with programmable parallel cryogen spray cooling bursts. RESULTS: Patients were assessed 1 day, 1 week, 4 months, and 6 months after treatment. Treatments were well tolerated, and no patient required pain control pre or post operatively. Mild erythema and edema were noted immediately after treatment and typically cleared within 2-3 days. Superficial, branny hyperpigmentation occurred in six patients at both treatment and control sides. This discoloration resolved within 1 week of treatment and left no residual pigment alterations. No whitening or residual scarring occurred. Rhytid scores improved from a baseline score of 2.3 to 1.8 at 6 months after treatment (p>0.05). Patient acceptance of the treatment was high, but most felt that there was little improvement of the treated rhytids. CONCLUSION: Although the 1.45 microm diode laser is capable of targeting dermal collagen and stimulating fibrosis at depths where solar elastosis resides, clinical improvement of rhytids was mild and did not correlate well with the degree of histologic changes noted in phase I.