Search

Background and objectives Successful outcomes of clinical studies for acne vulgaris depend greatly on achieving statistically significant reduction in acne lesion count and improvement in Investigator's Global Assessment score of the investigational drug product against its vehicle control. To date, there has not been a validated preclinical acne model to evaluate investigational drug products in order to improve the probability of clinical success. An inflammatory acne-like lesion mouse model developed in-house has previously been used for clinical guidance in our drug development program. In this study, we aim to implement and assess the adequacy of swept-source optical coherence tomography (SS-OCT) in quantifying the dynamic changes in inflammatory acne-like lesions. Study design/materials and methods Live Propionibacterium acnes bacteria were injected intradermally resulting in inflammatory acne-like lesions. Topical 1% and 2% minocycline gels were applied to the lesions in separate groups once daily for 2 weeks and compared with vehicle and untreated control groups. The growth of these lesions was monitored and measured with a ruler (height)/microcaliper (width)-an approach previously developed, and with SS-OCT. The reliability of the two methods were assessed. Acquired OCT images across the apex of these inflammatory lesions were statistically analyzed for lesion volume reduction from baseline as well as between the treatment groups and the control groups. Results The OCT technique allowed for reliable lesion volume analysis with varying conic profiles. After 14 days of topical minocycline treatments (1%, 2% minocycline), statistically significant reduction in lesion volume (P ≤ 0.05) based on OCT image analysis was observed compared with untreated and vehicle control groups as well as compared with baseline measurements. Under the right conditions, some morphological aspects of the P. acnes injection site were discernible within the skin in images captured with OCT. Conclusions We demonstrated the first use of SS-OCT in evaluating in vivo inflammatory acne-like lesions in a murine model. Our findings support the use of OCT in assessing lesion size and evolution of P. acnes injection sites non-invasively in preclinical in vivo studies, which could potentially lead to more consistent and predictable outcomes in clinical development. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

We recently proposed a method for selective visualization of topical drug distribution within human facial skin using two-photon fluorescence lifetime imaging along with non-Euclidean phasor analysis as a pharmacokinetics and pharmacodynamics imaging toolkit. In order to improve the efficacy of topical drug delivery toward the treatment of inflammatory acne, we have now developed a combination topical gel containing both minocycline and a retinoid. Since both drugs have unique fluorescence lifetimes compared to skin, we were able to selectively visualize the distribution of minocycline and the retinoid within ex vivo human facial skin while isolating the contributions of the three components.

Graphical abstract, Acne vulgaris is a clinically distinct skin condition with evidence suggesting that inflammation plays a critical role in the pathogenesis of this disorder. Treatment of severe inflammatory acne often involves the use of oral antibiotics, sometimes in combination with topical products. Oral antibiotics often result in systemic side effects and the risks of antibiotic resistance, but no commercial topical minocycline is currently available. We have developed a unique, stable, hydrophilic topical gel formulation with fully solubilized minocycline (MNC-H). Minocycline delivered in our hydrophilic gel remained more stable in situ, resulting in less degradation product (4-epiminocycline) than a lipophilic formulation (MNC-L). The hydrophilic nature of our formulation enabled 2–3 fold increase in delivery into the skin ex vivo compared to a lipophilic counterpart, mostly seen in the epidermis and pilosebaceous units. The lipophilic formulation also appeared to be more occlusive, resulting in higher sebum production in minipigs, which may exacerbate acne vulgaris. As our results indicate, a 1, 2% minocycline hydrophilic gel may deliver sufficient drug (>15 μg/g) to potentially demonstrate clinical efficacy. These findings suggest that topical hydrophilic minocycline gel may provide a novel tool for topical acne therapy.

Oral minocycline has been the standard of care for the treatment of non-nodular moderate to severe inflammatory acne vulgaris due to its inhibitory effects on the acne-causing Propionibacterium acnes bacterium and its anti-inflammatory properties, Despite the availability of an oral dosage form since 1966, a commercial topical minocycline remains elusive because of the challenges in stabilizing the active pharmaceutical ingredient (API) in a liquid/semisolid while ensuring sufficient uptake into targeted lesions. Recently, an investigative topical minocycline gel (BPX-01) has been developed to address the unmet needs for localized and targeted delivery while minimizing the risks of systemic side effects. Earlier preclinical studies pertaining to transepidermal delivery of the API had depended on semi-infinite doses of the 1%, 2% and 4% formulations to elicit enough fluorescence yield. We have subsequently shown evidence of minocycline delivery of 1% and 4% BPX-01 into the pilosebaceous unit of ex vivo human facial skin specimens dosed with about 2.5× daily dose using two-photon excitation fluorescence microscopy. In this study, we demonstrated another novel approach to identifying minocycline fluorescence signature using fluorescence lifetime imaging microscopy (FLIM) with phasor analysis. It was found that for a single daily dose and with FLIM, minocycline was consistently noted in the epidermis and hair follicle, with some incidence in the sebaceous gland for both 1% and 2% BPX-01. These observations corroborated with the recent success of a Phase 2b dose-finding study, with 2% BPX-01 meeting the primary endpoint of lesion reduction at week 12 with statistical significance over the vehicle.

Acne vulgaris is a chronic inflammatory skin condition commonly resulting in negative aesthetic and social impacts on those affected. Minocycline, currently available as an oral antibiotic for moderate to severe acne, has a known minimum inhibitory concentration (MIC) for the acne-causing bacterium Propionibacterium acnes (P. acnes) in vitro, with its anti-inflammatory properties also eliciting inhibitory effects on pro-inflammatory molecules. A novel topical gel composition containing solubilized minocycline (BPX-01) has been developed to directly deliver the drug to the skin. Because minocycline is a known fluorophore, fluorescence microscopy and concurrent quantitative measurements were performed on excised human facial skin dosed with different concentrations, in order to determine the spatial distribution of the drug and quantification of its local concentration in the epidermis and the pilosebaceous unit where P. acnes generally reside. Local minocycline delivery confirmed achievement of an adequate therapeutic dose to support clinical studies. Subsequently, a 4-week double-blind, randomized, vehicle controlled clinical study was performed to assess the safety and efficacy of 1% minocycline BPX-01 applied daily. No instances of cutaneous toxicity were reported, and a greater than 1 log reduction of P. acnes count was observed at week 4 with statistical significance from baseline and vehicle control. In addition, no detectable amounts of minocycline in the plasma were reported, suggesting the potential of this new formulation to diminish the known systemic adverse effects associated with oral minocycline. Follow-on clinical plans are underway to further establish the safety of BPX-01 and to evaluate its efficacy against inflammatory acne lesions in a 225 patient multi-center dose-finding study.

Minocycline is an antibiotic regularly prescribed to treat acne vulgaris. The only commercially available minocycline comes in an oral dosage form, which often results in systemic adverse effects. A topical minocycline composition (BPX-01) was developed to provide localized and targeted delivery to the epidermis and pilosebaceous unit where acne-related bacteria, Propionibacterium acnes (P. acnes), reside. As minocycline is a known fluorophore, fluorescence microscopy was performed to investigate its potential use in visualizing minocycline distribution within tissues. BPX-01 with various concentrations of minocycline, was applied topically to freshly excised human facial skin specimens. Spatial distribution of minocycline and its fluorescence intensity within the stratum corneum, epidermis, dermis, and pilosebaceous unit were assessed. The resulting fluorescence intensity data as a function of minocycline concentration may indicate clinically relevant therapeutic doses of topical BPX-01 needed to kill P. acnes and reduce inflammation for successful clinical outcomes.

Acne vulgaris is a common chronic skin disease in young adults caused by infection of the pilosebaceous unit, resulting in pimples and possibly permanent scarring on the skin. Minocycline, a common antibiotic, has been widely utilized as a systemic antimicrobial treatment for acne via oral administration. Recently, a topical minocycline gel (BPX-01) was developed to directly deliver minocycline through the epidermis and into the pilosebaceous unit to achieve localized treatment with lower doses of drug. As the effectiveness of the drug is directly related to its successful delivery, there is a need to evaluate the pharmacokinetics at the cellular level within tissue. Advantageously, minocycline is naturally fluorescent and can be directly visualized using microscopy-based approaches. Due to high endogenous autofluorescence, however, imaging of weakly emitting fluorescent molecules such as minocycline in skin tissue can be challenging. Here, we demonstrate a method for the selective visualization of minocycline within human skin tissue by utilizing two-photon excitation fluorescence (TPEF) microscopy and fluorescence lifetime imaging microscopy (FLIM). To demonstrate the feasibility of this approach, ex vivo human facial skin samples treated with various concentrations of BPX-01 were investigated. From the TPEF analysis, we were able to visualize relatively high levels of drug uptake within facial skin. However, minocycline fluorescence could be overwhelmed by endogenous fluorescence that complicates TPEF quantitative analysis, making FLIM more advantageous for visualizing drug uptake. Importantly, we found a unique signature of minocycline uptake via FLIM analysis that enabled the successful differentiation of the drug and enabled the extraction of drug local distribution from the endogenous fluorescence using a non-Euclidean phasor analysis method. Based on these results, we believe that the drug local distribution visualization method using TPEF and FLIM with phasor analysis can play an important role in studying the pharmacokinetics and pharmacodynamics of a topically applicable drug.

We tested the hypothesis that the mechanism of long pulse erbium:YAG laser lithotripsy is photothermal.Human urinary calculi were placed in deionized water and irradiated with erbium:YAG laser energy delivered through a sapphire optical fiber. Erbium:YAG bubble dynamics were visualized with Schlieren flash photography and correlated to acoustic emissions measured by a polyvinylidene fluoride needle hydrophone. The sapphire fiber was placed either parallel or perpendicular to the calculus surface to assess the contribution of acoustic transients to fragmentation. Stones were irradiated using desiccated stone irradiated in air, hydrated stone irradiated in air and hydrated stone irradiated in water. Ablation crater sizes were compared. Uric acid stones were irradiated in water and the water was assayed for cyanide.During the early phase of vapor bubble expansion, acoustic transients had minimal effects on calculus fragmentation. Fragmentation occurred due to direct absorption of laser energy transmitted to the calculus through the vapor channel between the sapphire fiber tip and calculus. The forward axial expansion of the bubble occurred more rapidly than the radial expansion. A parallel oriented fiber on the calculus surface produced no fragmentation but generated larger amplitude acoustic transients compared to perpendicular orientation. In perpendicular orientation the erbium:YAG laser did not generate any collapse acoustic waves but fragmentation occurred. Crater width was greatest for desiccated stones irradiated in air (p0.03). Cyanide production increased as erbium:YAG irradiation of uric acid calculi increased, (r2 = 0.98).The erbium:YAG laser fragments stones through a photothermal mechanism.

Not AvailableStudy supported by BioPharmX.

Each year, over 1.7 million women are diagnosed with breast cancer worldwide and about 35% of these diagnosed are expected to die from the disease. A significant barrier to improving treatment of breast cancer lies in our incomplete understanding of breast cancer initiation and metastasis. Regular use of molecular iodine has been shown to reduce the sensitivity of breast cells to the proliferative effects of estrogen, resulting in normalization of breast tissue.The aim of the current study was to evaluate the mechanisms of molecular iodine on two common breast cancer sub-types using well-established breast cancer cell lines. In order to study Luminal A and triple-negative breast cancer in vitro, MCF7 (cells from a luminal A subtype) and MDA-MB231 (cells from a triple-negative subtype), were treated with molecular iodine at various concentrations to measure proliferation and cell death. This was subsequently followed by gene expression analysis of key important molecular markers, which are primarily responsible for cell growth and apoptosis. Primary human mammary epithelial cells derived from healthy female donor were used as an internal control. Data from this study indicated that molecular iodine had potent inhibitory effects on cell growth and showed a dramatic increase in cell death in both breast cancer cell lines. Gene expression analysis using quantitative RT-PCR further confirmed that cell cycle genes controlling G1-S phase transition were largely up-regulated. Changes were not seen in Cyclin B expression levels, which further suggest that cells were arrested before entry into cell division. BCL-2, PPAR-α and PPAR-γ were also up-regulated along with down-regulation of Caspase 3, suggesting molecular iodine induced cell death through activation of a caspase-independent apoptosis pathway. Interestingly, mesenchymal-epithelial transition (MET) occurrence was noticed upon molecular iodine treatment as indicated by sharp increase of GATA3 and E-Cadherin and significant down-regulation of Vimentin in invasive MDA-MB231 cells. Our current study enables us to understand a molecular mechanism controlling tumor cell growth and demonstrates potent cellular effects of molecular iodine on breast cancer cell lines. These results also demonstrate promising effects of molecular iodine for regulation of breast cancer EMT differentiation, which is required for tumor initiation and metastasis. Further studies are underway to determine possible effects of molecular iodine in these breast cancer subtypes using in vitro 3D models. Note: This abstract was not presented at the meeting. Citation Format: Zack Xu, Xin Chen, Noymi Yam, kin Chan, Usha Nagavarapu. Elucidating the mechanism of action of molecular iodine on breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2243. doi:10.1158/1538-7445.AM2017-2243

Purpose: We test the hypothesis that erbium:YAG (Er:YAG) lithotripsy is more efficient than holmium:YAG (Ho:YAG) lithotripsy.Materials and Methods: Human calculi composed of greater than 97% calcium oxalate monohydrate and cystine were studied. Calculi were irradiated in water using Er:YAG or Ho:YAG lasers. Er:YAG lithotripsy was done with a 425 μm. sapphire optical fiber at a pulse energy of 50 mJ. at 10 Hz. Ho:YAG lithotripsy was performed with a 365 μm. low hydroxy optical fiber at a pulse energy of 500 mJ. at 10 Hz. or a 425 μm. sapphire optical fiber at a pulse energy of 50 mJ. at 10 Hz. Fragmentation was defined as the initial stone mass minus the final dominant fragment mass and normalized for incident laser fluence (energy per unit area of fiber tip).Results: Mean fragmentation plus or minus standard deviation for calcium oxalate monohydrate was 38 ± 27 mg. for Er:YAG and 22 ± 6 for Ho:YAG (low hydroxy silica fiber) versus 5 ± 1 for Ho:YAG (sapphire fiber, p = 0.001). When fragmentation was normal...

Infrared laser ablation of urinary calculi was investigated as a function of wavelength to determine the relation of ablation threshold fluences, ablation depths, and optical absorption. A simple photothermal ablation model was employed to examine this relationship. Human urinary calculi composed of >95% uric acid, >95% cystine, >95% calcium oxalate monohydrate (COM), and >90% magnesium ammonium phosphate hexahydrate (MAPH) were used. Various wavelengths between 2.1 and 6.5 /spl mu/m were selected to perform threshold fluence and ablation depth measurements. The laser source for this study was the tunable pulsed infrared free electron laser (FEL) at Vanderbilt University. Experimental results indicated a correlation of threshold fluence and ablation depth to the optical absorption properties of the calculi. When calculus optical absorption increased, the threshold fluences decreased. Although the ablation depths increased with calculus optical absorption, results indicated that in certain calculi the ablation depth was affected by optical attenuation through the ablation plume. These observations were in agreement with the photothermal ablation model, but fractures in striated calculi at higher optical absorptions indicated the contribution of a photomechanical mechanism.

The pulsed holmium:YAG laser (lambda = 2.12 microm, tau(p) = 250 micros) has been investigated as a method for inducing localized coagulation for medical procedures, yet the dynamics of this process are not well understood. In this study, photocoagulation of albumen (egg white) was analysed experimentally and results compared with optical-thermal simulations to investigate a rate process approach to thermal damage and the role of heat conduction and dynamic changes in absorption. The coagulation threshold was determined using probit analysis, and coagulum dynamics were documented with fast flash photography. The nonlinear computational model, which included a Beer's law optical component, a finite difference heat transfer component and an Arrhenius equation-based damage calculation, was verified against data from the literature. Moderate discrepancies between simulation results and our experimental data probably resulted from the use of a laser beam with an irregular spatial profile. This profile produced a lower than expected coagulation threshold and an irregular damage distribution within a millisecond after laser onset. After 1 ms, heat conduction led to smoothing of the coagulum. Simulations indicated that dynamic changes in absorption led to a reduction in surface temperatures. The Arrhenius equation was shown to be effective for simulating transient albumen coagulation during pulsed holmium:YAG laser irradiation. Greater understanding of pulsed laser-tissue interactions may lead to improved treatment outcome and optimization of laser parameters for a variety of medical procedures.

A series of experiments were conducted to test the hypothesis that the mechanism of holmium:YAG lithotripsy is photothermal.To show that holmium:YAG lithotripsy requires direct absorption of optical energy, stone loss was compared for 150 J Ho:YAG lithotripsy of calcium oxalate monohydrate (COM) stones for hydrated stones irradiated in water (17+/-3 mg) and hydrated stones irradiated in air (25+/-9 mg) v dehydrated stones irradiated in air (40+/-12 mg) (P0.001). To show that Ho:YAG lithotripsy occurs prior to vapor bubble collapse, the dynamics of lithotripsy in water and vapor bubble formation were documented with video flash photography. Holmium:YAG lithotripsy began at 60 microsec, prior to vapor bubble collapse. To show that Ho:YAG lithotripsy is fundamentally related to stone temperature, cystine, and COM mass loss was compared for stones initially at room temperature (approximately 23 degrees C) v frozen stones ablated within 2 minutes after removal from the freezer. Cystine and COM mass losses were greater for stones starting at room temperature than cold (Por = 0.05). To show that Ho:YAG lithotripsy involves a thermochemical reaction, composition analysis was done before and after lithotripsy. Postlithotripsy, COM yielded calcium carbonate; cystine yielded cysteine and free sulfur; calcium hydrogen phosphate dihydrate yielded calcium pyrophosphate; magnesium ammonium phosphate yielded ammonium carbonate and magnesium carbonate; and uric acid yielded cyanide. To show that Ho:YAG lithotripsy does not create significant shockwaves, pressure transients were measured during lithotripsy using needle hydrophones. Peak pressures were2 bars.The primary mechanism of Ho:YAG lithotripsy is photothermal. There are no significant photoacoustic effects.

Background and Objective Evidence is presented that the fragmentation process of long-pulse Holmium:YAG (Ho:YAG) lithotripsy is governed by photothermal decomposition of the calculi rather than photomechanical or photoacoustical mechanisms as is widely thought. The clinical Ho:YAG laser lithotriptor (2.12 μm, 250 μs) operates in the free-running mode, producing pulse durations much longer than the time required for a sound wave to propagate beyond the optical penetration depth of this wavelength in water. Hence, it is unlikely that shock waves are produced during bubble formation. In addition, the vapor bubble induced by this laser is not spherical. Thus the magnitude of the pressure wave produced at cavitation collapse does not contribute significantly to lithotripsy. Study Design/Materials and Methods A fast-flash photography setup was used to capture the dynamics of urinary calculus fragmentation at various delay times following the onset of the Ho:YAG laser pulse. These images were concurrently correlated with pressure measurements obtained with a piezoelectric polyvinylidene-fluoride needle-hydrophone. Stone mass-loss measurements for ablation of urinary calculi (1) in air (dehydrated and hydrated) and in water, and (2) at pre-cooled and at room temperatures were compared. Chemical and composition analyses were performed on the ablation products of several types of Ho:YAG laser irradiated urinary calculi, including calcium oxalate monohydrate (COM), calcium hydrogen phosphate dihydrate (CHPD), magnesium ammonium phosphate hexahydrate (MAPH), cystine, and uric acid calculi. Results When the optical fiber was placed perpendicularly in contact with the surface of the target, fast-flash photography provided visual evidence that ablation occurred approximately 50 μs after the initiation of the Ho:YAG laser pulse (250–350 μs duration; 375–400 mJ per pulse), long before the collapse of the cavitation bubble. The measured peak acoustical pressure upon cavitation collapse was negligible (< 2 bars), indicating that photomechanical forces were not responsible for the observed fragmentation process. When the fiber was placed in parallel to the calculus surface, the pressure peaks occurring at the collapse of the cavitation were on the order of 20 bars, but no fragmentation occurred. Regardless of fiber orientation, no shock waves were recorded at the beginning of bubble formation. Ablation of COM calculi (a total of 150 J; 0.5 J per pulse at an 8-Hz repetition rate) revealed different Ho:YAG efficiencies for dehydrated calculus, hydrated calculus, and submerged calculus. COM and cystine calculi, pre-cooled at −80°C and then placed in water, yielded lower mass-loss during ablation (20 J, 1.0 J per pulse) compared to the mass-loss of calculi at room temperature. Chemical analyses of the ablated calculi revealed products resulting from thermal decomposition. Calcium carbonate was found in samples composed of COM calculi; calcium pyrophosphate was found in CHPD samples; free sulfur and cysteine were discovered in samples composed of cystine samples; and cyanide was found in samples of uric acid calculi. Conclusion These experimental results provide convincing evidence that long-pulse Ho:YAG laser lithotripsy causes chemical decomposition of urinary calculi as a consequence of a dominant photothermal mechanism. Lasers Surg. Med. 25:22–37, 1999. © 1999 Wiley-Liss, Inc.

467 Background: There is an unmet need for a comprehensive genomic characterization of non muscle invasive bladder cancer (NMIBC). NMIBC comprise over 70% of all bladder cancers at presentation. They have highly variable clinical behavior that is not always adequately predicted on the basis of their histological grade (2004 World Health Organization low and high grade, LG-HG). The discrepancy between phenotype and genotype is compounded further by interobserver variability in pathological grading. We have previously established methods for whole transcriptome RNAseq from formalin fixed paraffin embedded tissues (FFPE). Methods: Whole transcriptomic analysis of 110 NMI FFPE BC both LG and HG was performed incorporating messenger RNA expression, splice variants, gene fusion, and pathway perturbation. We used a discovery (n = 40) and a validation cohort (n = 70). These data were integrated and tested for correlation with both pathological grading and clinical outcomes. Grade Risk Index (GRI) score quantifying how closely a patient's transcriptome is related to a reference set of LG NMIBC samples was established. Conventional pathological grading was reviewed by 3 different expert uro-pathologists and interobserver variability calculated. Results: Unsupervised clustering of data from RNA sequencing uncovered classification of three robust - - nonoverlapping, prognostically significant subtypes of NMIBC with distinct GRIs and signatures. When applied by expert pathologists, interobserver variability in histological grading was observed in 17.5%. In the intermediate group (GRI 0.13 to 0.19), pathologists disagreed in 37.5% whether BC was LG or HG. HG NMIBC clustered with MIBC. LG NMIBC in the intermediate GRI group included either very bulky tumors or extremely rare metastatic LG BC (n = 4). HG disease was associated with a shift in BMP signaling and a germ stem cell-like phenotype. Multiple components of the centromere complex and APOBEC3B were upregulated in HG BC. FGFR3::TACC3 fusion events were observed in LG NMIBC only (11.5%). Conclusions: Whole transcriptomic sequencing data delineated three molecular classes of NMIBC.

Light emitted from a femtosecond laser is capable of plasma-induced ablation of various materials. We tested the feasibility of utilizing femtosecond-pulsed laser radiation =800 nm, 140 fs, 0.9 mJ/pulse for ablation of urinary calculi. Ablation craters were observed in human calculi of greater than 90% calcium oxalate monohydrate COM, cystine CYST, or magnesium ammonium phosphate hexahydrate MAPH. Largest crater volumes were achieved on CYST stones, among the most difficult stones to fragment using Holmium:YAG Ho:YAG lithotripsy. Diameter of debris was characterized using optical microscopy and found to be less than 20 m, substantially smaller than that produced by long-pulsed Ho:YAG ablation. Stone retropulsion, monitored by a high-speed camera system with a spatial resolution of 15 m, was negligible for stones with mass as small as 0.06 g. Peak shock wave pressures were less than 2 bars, measured by a polyvinylidene fluoride PVDF needle hydrophone. Ablation dynamics were visualized and charac- terized with pump-probe imaging and fast flash photography and cor- related to shock wave pressures. Because femtosecond-pulsed laser ablates urinary calculi of soft and hard compositions, with micron- sized debris, negligible stone retropulsion, and small shock wave pressures, we conclude that the approach is a promising candidate technique for lithotripsy. © 2010 Society of Photo-Optical Instrumentation Engineers.

Background and Objective: Due to the significant risk profile associated with traditional ablative resurfacing, a safer and less invasive treatment approach known as fractional deep dermal ablation (FDDA™) was recently developed. We report the results of the first clinical investigation of this modality for treatment of photo- damaged skin. Study Design/Materials and Methods: Twenty-four subjects received treatments on the inner forearm with a prototype fractional CO2laser device (Reliant Technologies Inc., Mountain View, CA) at settings of 5-40 mJ/MTZ and 400 MTZ/cm2. Clinical and histological effects were assessed by study investigators 1 week, 1 month, and 3 months following treatment. Thirty subjects were then enrolled in a multi-center study for treatment of photo- damage using the same device. Subjects received 1-2 treatments on the face and neck, with energies ranging from 10 to 40 mJ/MTZ and densities ranging from 400 to 1,200 MTZ/cm2. Study investigators assessed severity of post-treatment responses during follow-up visits 48 hours, 1 week, 1 month, and 3 months following treatment. Using a standard quartile improvement scale (0-4), subjects and investigators assessed improvement in rhytides, pigmentation, texture, laxity and overall appearance 1 and 3 months post-treatment. Results: Clinical and histologic results demonstrated that fractional delivery of a 10,600 nm CO2laser source offers an improved safety profile with respect to traditional ablative resurfacing, while still effectively resurfacing epidermal and dermal tissue. Forearm and facial treatments were well-tolerated with no serious adverse events observed. Eighty-three percent of subjects exhibited moderate or better overall improvement (50-100%), according to study investigator quartile scoring. Conclusions: FDDA™ treatment is a safe and promising new approach for resurfacing of epidermal and deep dermal tissue targets. Lasers Surg © 2009 Wiley-Liss, Inc.

An innovative High Resolution Maskless Lithography System (Hi-Res MLS) was designed using Texas Instruments’ SVGA DMD, which employs additional micro-optics with a combination of low and high NA projection lens systems. A low power mercury-arc lamp filtered for G-line (λ = 435.8 nm) was used as the light source. Exposure experiments were performed using Ball patented Point Array scrolling or scanning method and proprietary data conversion, extraction and transfer software algorithms. In each scan, the field-width (W) was approximately 8.47 mm with the field-length (longitudinal field) only limited by memory capacity. DMD frame rates of up to 5 kHz (kframe/s) were achievable, which were synchronized to the stage motion. In this experiment, TSMR-8970XB10 photo-resist, diluted to 3.8 cP with PR thinner was employed. The photo-resist was spin-coated on a glass substrate to 1.0-μm thickness with 0.1-μm uniformity. A 0.4-μm step-size was used and 27000 DLP frames were extracted and transferred to the DMD driver. Results indicated consistent 1.8 μm L/S resolved across the entire field-width of 8.47 mm. At certain locales, 1.5-μm L/S was also resolved. The potential of this maskless lithography system is substantial. Even at the current level of performance, the system is sufficient for applications in MEMS, MOEMS, photomasking, high resolution LCD, high density PCB, etc. Higher productivity is predicted by lens system designed for H-line (λ = 405 nm), by using Ball’s violet diode laser systems, and the development of real-time driver.

For typically small volume production of MEMS, MOEMS, fine feature PCB, high density chip packaging and display panels, especially for lab tests, low cost and the capability to change the original design easily and quickly are very important for customers and researchers. BALL Semiconductor Inc.'s Maskless Lithography Systems (MLS) feature the Digital Mirror Device (DMD) as the pattern generator to replace photo-masks. This can remove masks from UV lithography, and dramatically reduce the running cost and save time for lab tests and small volume production. At Ball Semiconductor Inc, 1.5μm line/space, 10μm line/space, and 20μm line/space Maskless Lithography Systems were developed. In our MLS, an 848×600 microlens and spatial filter array (MLSFA) was used to focus the light and to filter the noise. In order to produce smaller line-space than 16μm the MLSFA was used to get smaller UV light pad (compared with the SVGA DMD’s micro-mirror: 17μm×17μm) and to filter the noise produced from the DMD, optical lens system, and micro lens array. This MLSFA is one of the key devices for our Maskless Lithography System, and determines the resolution and quality of maskless lithography. A novel design and fabrication process of a single-package MLSFA for our Maskless Lithography System will be introduced. To avoid problems produced by misalignment between a two-piece spatial filter and microlens array, MEMS processing is used to integrate the microlens array with the spatial filter array. In this paper, the self-alignment method used to fabricate exactly matched MLSFA will be presented.

This paper describes in simple terms the physics of laser-calculus interactions and introduces a method with which physicians can understand or evaluate the application of any new laser technique for use in lithotripsy or other medical fields. Tissue optical properties and laser parameters govern the mechanism(s) of fragmentation of urinary or biliary calculi. Laser pulse energies for clinical lithotripsy range from Q0 = 20 mJ to 2 J for short-pulsed lasers to long-pulsed lasers, respectively. Lasers with short pulse durations (i.e., less than a few microseconds) fragment calculi by means of shockwaves following optical breakdown and plasma expansion of ionized water or calculus compositions or by cavitation collapse, thus manifesting a photoacoustical effect. Laser-tissue interactions involving dominant photomechanical or photoacoustical effects are usually stress confined. Long-pulsed lasers (i.e., >100 microsec), on the other hand, generate minimal acoustic waves, and calculi are fragmented by temperatures beyond the thresholds for vaporization of calculus constituents, melting, or chemical decomposition.

The potential application of an Erbium:YAG (Er:YAG) laser (Q 0 = 50 mJ/pulse; τ p = 275 μs; rep. rate = 2, 10 Hz) with a sapphire delivery fiber for intracorporeal laser lithotripsy was explored. Preliminary measurements on calculus mass-loss and fragmentation efficiency were conducted and results were compared with that of Ho:YAG laser lithotripsy. Laser induced bubble and lithotripsy dynamics were investigated to assess the mechanism(s) involved in the fragmentation process. Results showed that the fragmentation efficiency (mass-loss/H o - g.μm 2 /J) in Er:YAG laser lithotripsy was about 2.4 times that of Ho:YAG laser lithotripsy (used: Q 0 = 500 mJ/pulse; Tp = 250 μs; rep. rate = 10 Hz). Acoustic transients were found to have minimal effect during Er:YAG laser lithotripsy. Schlieren flash images suggested a predominantly photothermal mechanism due to direct laser energy absorption, which resulted in recrystallization and plume formation. These events indicated melting and chemical decomposition of the calculus composition. Another observation led to the possibility of a plasma-mediated photothermal mechanism. The 'Moses effect' facilitating pulsed mid-infrared laser delivery appeared more efficient for the Er:YAG laser than for the Ho:YAG laser. With the sapphire fiber, experimental results suggested the potential of an improved treatment modality by the Er:YAG laser for intracorporeal laser lithotripsy.

The objectives of this study were to determine if the optical absorption properties of urinary calculi affect thethreshold fluence for ablation or fragmentation and the ablation efficiency due to laser irradiation. The Vanderbiltfree electron laser (FEL) was tuned to selected wavelengths based on the absorption spectrum of various types ofurinary calculi. The threshold fluences for ablation of the calculi were measured at different wavelengths. Apreliminary study of the ablation efficiency (ablation depth per unit incidence fluence) was performed. The resultswere found to be in agreement with a thermal ablation model for which the threshold fluences were proportional to 1/J.ta. The ablation efficiencies were higher in regions of the infrared spectra in which absorption was higher. For afixed laser irradiation, the lower threshold fluences within regions of high optical absorption allowed more energy toenhance calculus ablation. This study provided insight into determining the optimum wavelengths for ablation andlaser lithotripsy.Keywords: ablation efficiency, absorption coefficient, fragmentation efficiency, free electron laser, infrared, kidneystone, optimum wavelength, threshold radiant exposure, tissue ablation.

To determine the threshold radiant exposures (J/cm2) needed for ablation or fragmentation as a function of infrared wavelengths on various urinary calculi and to determine if there is a relation between these thresholds and lithotripsy efficiencies with respect to optical absorption coefficients.Human calculi composed of uric acid, calcium oxalate monohydrate (COM), cystine, or magnesium ammonium phosphate hexahydrate (MAPH) were used. The calculi were irradiated in air with the free electron laser (FEL) at six wavelengths: 2.12, 2.5, 2.94, 3.13, 5, and 6.45 microm.Threshold radiant exposures increased as optical absorption decreased. At the near-infrared wave-lengths with low optical absorption, the thresholds were1.5 J/cm2. The thresholds decreased below 0.5 J/cm2 for regions of high absorption for all the calculus types. Thresholds within the high-absorption regions were statistically different from those in the low-absorption regions, with P values much less than 0.05.Optical absorption coefficients or threshold radiant exposures can be used to predict lithotripsy efficiencies. For low ablation thresholds, smaller radiant exposures were required to achieve breakdown temperatures or to exceed the dynamic tensile strength of the material. Therefore, more energy is available for fragmentation, resulting in higher lithotripsy efficiencies.

The Ho:YAG laser commonly used for clinical lithotripsy of urinary stones typically emits 250-microsecond pulses at a wavelength of 2.12 micrometer and repetition rates of up to 10 Hz. This pulse duration is longer than the time required for a pressure wave to propagate beyond the optical penetration depth of this wavelength in water. Fast-flash photography was used to study the dynamics of urinary stone fragmentation by the Ho:YAG laser. Stone ablation began approximately 50 microseconds after the onset of the laser pulse, long before the collapse of the cavitation bubble at about 350 microseconds. Pressure measurements, made with a PVDF needle- hydrophone and correlated with the fast-flash images, indicated that the peak acoustical transient was less than 2 bars. Regardless of fiber orientation to the stone, no shockwaves were recorded at the beginning of the bubble, and the maximum pressure waves recorded at bubble collapse were approximately 20 bars. However, no fragmentation occurred during or subsequent to the bubble collapse. The measurements indicated that stone ablation was not due to a photomechanical effect.

The development of thermal damage during pulsed Holmium:YAG (2 — 2. 12 pm, t = 250 s) irradiation of albumen was analyzed experimentally and nmnencally with the intent of validating the Arrhemus integral and investigating the influence of beam profile and dynamic changes in absorption. Fast flash videography wasperformed to document the transient development of coagulation during and after the laser pulse. A two- dimensional dynamic optical-thermal model was developed.The optical component involved a discretized Beer's law method in which absorption is a function of temperature.The thermal component was comprised of 1) a cylindrical coordinate (r,z) finite difference formulation of the heatconduction equation in which the output from the optical model was used as the source term and 2) a routine forcalculating thermal damage using the Arrhenius relation. At the end of each time step, the temperature thstributionwas used to recalculate the absorption coefficient array, which in turn is used in the optical component.The model showed good agreement with experimental data and the literature. The Arrhemus integral was shown tobe valid for the sub-vaporization pulsed laser regime. Experimental and numerical results indicated that spatialbeam profile has a significant impact on thermal damage. Simulations predicted that at higher radiant exposuresdynamic changes in absorption become more significant, accounting for a 10% increase in coagulation depth.Keywords: thermal damage, albumen, pulsed holmium laser, laser-tissue interaction, high speed imaging, heattransfer, dynamic optical properties, numerical modeling, finite difference, Arrhemus integral

An innovative high-resolution maskless lithography system is designed employing a combination of low- and high-numerical-aperture (NA) projection lens systems along with integrated micro-optics, and using Texas Instruments' super video graphic array (SVGA) digital micromirror device (DMD) as the spatial and temporal light modulator. A mercury arc lamp filtered for the G-line (λ = 435.8 nm) is used as the light source. Exposure experiments are performed using data extraction and transfer software, and synchronous stage control algorithms derived from a point array scrolling technique. Each exposure scan produces a field width (W) of approximately 8.47 mm with a field length (longitudinal field) limited only by onboard memory capacity. DMD frame rates of up to 5 kHz (kframes/s), synchronized to the stage motion, are achievable. In this experiment, TSMR-8970XB10 photoresist (PR), diluted to 3.8 cP with PR thinner is prepared. The PR is spin-coated onto a chrome-coated glass substrate to 1.0-μm thickness with 0.1-μm uniformity. A 0.4-μm scan step is used and 27,000 DMD data frames are extracted and transferred to the DMD driver. Results indicate consistent 1.8-μm line space (L/S) resolved across the entire field width of 8.47 mm. Given optimized exposure and development conditions, 1.5-μm L/S is also observed at certain locations. The potential of this maskless lithography system is substantial; its performance is sufficient for applications in microelectromechanical systems (MEMS), photomasking, high-resolution LCD, high-density printed circuit boards (PCBs), etc. Higher productivity is predicted by a custom H-line (λ = 405 nm) lens system designed and used in conjunction with a violet diode laser systems and the development of a real-time driver.