Fractional CO(2) laser-assisted drug delivery.

BACKGROUND AND OBJECTIVES: Ablative fractional resurfacing (AFR) creates vertical channels that might assist the delivery of topically applied drugs into skin. The purpose of this study was to evaluate drug delivery by CO(2) laser AFR using methyl 5-aminolevulinate (MAL), a porphyrin precursor, as a test drug. MATERIALS AND METHODS: Two Yorkshire swine were treated with single-hole CO(2) laser AFR and subsequent topical application of MAL (Metvix(R), Photocure ASA, Oslo, Norway), placebo cream and no drug. MAL-induced porphyrin fluorescence was measured by fluorescence microscopy at skin depths down to 1,800 microm. AFR was performed with a 10.6 microm wavelength prototype CO(2) laser, using stacked single pulses of 3 millisecond and 91.6 mJ per pulse. RESULTS: AFR created cone-shaped channels of approximately 300 microm diameter and 1,850 microm depth that were surrounded by a 70 microm thin layer of thermally coagulated dermis. There was no porphyrin fluorescence in placebo cream or untreated skin sites. AFR followed by MAL application enhanced drug delivery with significantly higher porphyrin fluorescence of hair follicles (P<0.0011) and dermis (P<0.0433) versus MAL alone at skin depths of 120, 500, 1,000, 1,500, and 1,800 microm. AFR before MAL application also enhanced skin surface (epidermal) porphyrin fluorescence. Radial diffusion of MAL from the laser-created channels into surrounding dermis was evidenced by uniform porphyrin fluorescence up to 1,500 microm from the holes (1,000, 1,800 microm depths). Skin massage after MAL application did not affect MAL-induced porphyrin fluorescence after AFR. CONCLUSIONS: Ablative fractional laser treatment facilitates delivery of topical MAL deeply into the skin. For the conditions of this study, laser channels approximately 3 mm apart followed by MAL application could produce porphyrins throughout essentially the entire skin. AFR appears to be a clinically practical means for enhancing uptake of MAL, a photodynamic therapy drug, and presumably many other topical skin medications.

Subcutaneous Fat Reduction with Injected Ice Slurry.

BACKGROUND: Cryolipolysis is a noninvasive method for removal of subcutaneous fat for body contouring. Conventional cryolipolysis with topical cooling requires extracting heat from subcutaneous fat by conduction across the skin, thus limiting the amount and the location of the fat removed. The authors hypothesized that local injection of a physiological ice slurry directly into target adipose tissue would lead to more efficient and effective cryolipolysis. METHODS: Injectable slurries containing 20 percent and 40 percent ice content were made using common parenteral agents (normal saline and glycerol), then locally injected into the subcutaneous fat of swine. Ultrasound imaging, photography, histological, and gross tissue responses were monitored before and periodically up to 8 weeks after injection. RESULTS: Fat loss occurred gradually over several weeks following a single ice slurry injection. There was an obvious and significant 55 ± 6 percent reduction in adipose tissue thickness compared with control sites injected with the same volume of melted slurry (p < 0.001, t test). The amount of fat loss correlated with the total volume of ice injected. There was no scarring or damage to surrounding tissue. CONCLUSION: Physiological ice slurry injection is a promising new strategy for selective and nonsurgical fat removal.

Small blood vessel engineering.

Tissue engineering has attracted wide interest as a potential method to alleviate the shortage of transplantable organs (1). To date, almost all of the successfully engineered tissues/organs have relatively thin and/or avascular structures [e.g., skin (2), cartilage (3), and bladder (4)], where postimplantation vascularization from the host (angiogenesis) is sufficient to meet the implant's demand for oxygen and nutrients. Vascularization remains a critical obstacle impeding attempts to engineer thicker, metabolically demanding organs, such as heart and liver. One approach in vascularizing an engineered tissue is to add the cellular components of blood vessels (endothelial and perivascular cells) directly to the tissue-engineered construct. We have shown that coimplanting endothelial cells and perivascular cells in a scaffold in vivo can lead to the formation of a vascular network that anastomoses to the host circulatory system. The engineered vessels are stable and functional, and they persist for more than 1 year in vivo. This approach may potentially lead to the creation of a well-vascularized-engineered tissue.

PlGF/VEGFR-1 Signaling Promotes Macrophage Polarization and Accelerated Tumor Progression in Obesity.

PURPOSE: Obesity promotes pancreatic and breast cancer progression via mechanisms that are poorly understood. Although obesity is associated with increased systemic levels of placental growth factor (PlGF), the role of PlGF in obesity-induced tumor progression is not known. PlGF and its receptor VEGFR-1 have been shown to modulate tumor angiogenesis and promote tumor-associated macrophage (TAM) recruitment and activity. Here, we hypothesized that increased activity of PlGF/VEGFR-1 signaling mediates obesity-induced tumor progression by augmenting tumor angiogenesis and TAM recruitment/activity. EXPERIMENTAL DESIGN: We established diet-induced obese mouse models of wild-type C57BL/6, VEGFR-1 tyrosine kinase (TK)-null, or PlGF-null mice, and evaluated the role of PlGF/VEGFR-1 signaling in pancreatic and breast cancer mouse models and in human samples. RESULTS: We found that obesity increased TAM infiltration, tumor growth, and metastasis in pancreatic cancers, without affecting vessel density. Ablation of VEGFR-1 signaling prevented obesity-induced tumor progression and shifted the tumor immune environment toward an antitumor phenotype. Similar findings were observed in a breast cancer model. Obesity was associated with increased systemic PlGF, but not VEGF-A or VEGF-B, in pancreatic and breast cancer patients and in various mouse models of these cancers. Ablation of PlGF phenocopied the effects of VEGFR-1-TK deletion on tumors in obese mice. PlGF/VEGFR-1-TK deletion prevented weight gain in mice fed a high-fat diet, but exacerbated hyperinsulinemia. Addition of metformin not only normalized insulin levels but also enhanced antitumor immunity. CONCLUSIONS: Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression. Clin Cancer Res; 22(12); 2993-3004. ©2016 AACR.