Person: Golberg, Alexander
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Golberg
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Alexander
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Golberg, Alexander
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Publication Eradication of Multidrug-Resistant Pseudomonas Biofilm With Pulsed Electric Fields(Wiley, 2015-09-09) Khan, Saiqa I.; Blumrosen, Gaddi; Vecchio, Daniela; Golberg, Alexander; Hamblin, Michael; McCormack, Michael; Yarmush, Martin; Austen, WilliamBiofilm formation is a significant problem, accounting for over eighty percent of microbial infections in the body. Biofilm eradication is problematic due to increased resistance to antibiotics and antimicrobials as compared to planktonic cells. The purpose of this study was to investigate the effect of Pulsed Electric Fields (PEF) on biofilm-infected mesh. Prolene mesh was infected with bioluminescent Pseudomonas aeruginosa and treated with PEF using a concentric electrode system to derive, in a single experiment, the critical electric field strength needed to kill bacteria. The effect of the electric field strength and the number of pulses (with a fixed pulse length duration and frequency) on bacterial eradication was investigated. For all experiments, biofilm formation and disruption were confirmed with bioluminescent imaging and Scanning Electron Microscopy (SEM). Computation and statistical methods were used to analyze treatment efficiency and to compare it to existing theoretical models. In all experiments 1500V are applied through a central electrode, with pulse duration of 50s, and pulse delivery frequency of 2Hz. We found that the critical electric field strength (Ecr) needed to eradicate 100-80% of bacteria in the treated area was 121 +/- 14V/mm when 300 pulses were applied, and 235 +/- 6.1V/mm when 150 pulses were applied. The area at which 100-80% of bacteria were eradicated was 50.5 +/- 9.9mm(2) for 300 pulses, and 13.4 +/- 0.65mm(2) for 150 pulses. 80% threshold eradication was not achieved with 100 pulses. The results indicate that increased efficacy of treatment is due to increased number of pulses delivered. In addition, we that showed the bacterial death rate as a function of the electrical field follows the statistical Weibull model for 150 and 300pulses. We hypothesize that in the clinical setting, combining systemic antibacterial therapy with PEF will yield a synergistic effect leading to improved eradication of mesh infections.Publication Live single cell functional phenotyping in droplet nano-liter reactors(Nature Publishing Group, 2013) Konry, Tania; Golberg, Alexander; Yarmush, MartinWhile single cell heterogeneity is present in all biological systems, most studies cannot address it due to technical limitations. Here we describe a nano-liter droplet microfluidic-based approach for stimulation and monitoring of surfaceand secreted markers of live single immune dendritic cells (DCs) as well as monitoring the live T cell/DC interaction. This nano-liter in vivo simulating microenvironment allows delivering various stimuli reagents to each cell and appropriate gas exchanges which are necessary to ensure functionality and viability of encapsulated cells. Labeling bioassay and microsphere sensors were integrated into nano-liter reaction volume of the droplet to monitor live single cell surface markers and secretion analysis in the time-dependent fashion. Thus live cell stimulation, secretion and surface monitoring can be obtained simultaneously in distinct microenvironment, which previously was possible using complicated and multi-step in vitro and in vivo live-cell microscopy, together with immunological studies of the outcome secretion of cellular function.Publication Cloud-Enabled Microscopy and Droplet Microfluidic Platform for Specific Detection of Escherichia coli in Water(Public Library of Science, 2014) Golberg, Alexander; Linshiz, Gregory; Kravets, Ilia; Stawski, Nina; Hillson, Nathan J.; Yarmush, Martin; Marks, Robert S.; Konry, TaniaWe report an all-in-one platform – ScanDrop – for the rapid and specific capture, detection, and identification of bacteria in drinking water. The ScanDrop platform integrates droplet microfluidics, a portable imaging system, and cloud-based control software and data storage. The cloud-based control software and data storage enables robotic image acquisition, remote image processing, and rapid data sharing. These features form a “cloud” network for water quality monitoring. We have demonstrated the capability of ScanDrop to perform water quality monitoring via the detection of an indicator coliform bacterium, Escherichia coli, in drinking water contaminated with feces. Magnetic beads conjugated with antibodies to E. coli antigen were used to selectively capture and isolate specific bacteria from water samples. The bead-captured bacteria were co-encapsulated in pico-liter droplets with fluorescently-labeled anti-E. coli antibodies, and imaged with an automated custom designed fluorescence microscope. The entire water quality diagnostic process required 8 hours from sample collection to online-accessible results compared with 2–4 days for other currently available standard detection methods.Publication Tissue heterogeneity in structure and conductivity contribute to cell survival during irreversible electroporation ablation by “electric field sinks”(Nature Publishing Group, 2015) Golberg, Alexander; Bruinsma, Bote G.; Uygun, Basak; Yarmush, MartinIrreversible electroporation (IRE) is an emerging, minimally invasive technique for solid tumors ablation, under clinical investigation for cancer therapy. IRE affects only the cell membrane, killing cells while preserving the extracellular matrix structure. Current reports indicate tumors recurrence rate after IRE averaging 31% of the cases, of which 10% are local recurrences. The mechanisms for these recurrences are not known and new explanations for incomplete cell death are needed. Using finite elements method for electric field distribution, we show that presence of vascular structures with blood leads to the redistribution of electric fields leading to the areas with more than 60% reduced electric field strength in proximity to large blood vessels and clustered vessel structures. In an in vivo rat model of liver IRE ablation, we show that cells located in the proximity of larger vessel structures and in proximity of clustered vessel structures appear less affected by IRE ablation than cells in the tissue parenchyma or in the proximity of small, more isolated vessels. These findings suggest a role for “electric field sinks” in local tumors recurrences after IRE and emphasize the importance of the precise mapping of the targeted organ structure and conductivity for planning of electroporation procedures.Publication Skin Rejuvenation with Non-Invasive Pulsed Electric Fields(Nature Publishing Group, 2015) Golberg, Alexander; Khan, S; Belov, Vasily; Quinn, Kyle P.; Albadawi, Hassan; Felix Broelsch, G.; Watkins, Michael; Georgakoudi, Irene; Papisov, Mikhail; Mihm Jr., Martin C.; Austen Jr., William G.; Yarmush, MartinDegenerative skin diseases affect one third of individuals over the age of sixty. Current therapies use various physical and chemical methods to rejuvenate skin; but since the therapies affect many tissue components including cells and extracellular matrix, they may also induce significant side effects, such as scarring. Here we report on a new, non-invasive, non-thermal technique to rejuvenate skin with pulsed electric fields. The fields destroy cells while simultaneously completely preserving the extracellular matrix architecture and releasing multiple growth factors locally that induce new cells and tissue growth. We have identified the specific pulsed electric field parameters in rats that lead to prominent proliferation of the epidermis, formation of microvasculature, and secretion of new collagen at treated areas without scarring. Our results suggest that pulsed electric fields can improve skin function and thus can potentially serve as a novel non-invasive skin therapy for multiple degenerative skin diseases.Publication The Role of CHI3L1 (Chitinase-3-Like-1) in the Pathogenesis of Infections in Burns in a Mouse Model(Public Library of Science, 2015) Bohr, Stefan; Patel, Suraj; Vasko, Radovan; Shen, Keyue; Golberg, Alexander; Berthiaume, Francois; Yarmush, MartinIn severe burn injury the unique setting of a depleted, dysfunctional immune system along with a loss of barrier function commonly results in opportunistic infections that eventually proof fatal. Unfortunately, the dynamic sequence of bacterial contamination, colonization and eventually septic invasion with bacteria such as Pseudomonas species is still poorly understood although a limiting factor in clinical decision making. Increasing evidence supports the notion that inhibition of bacterial translocation into the wound site may be an effective alternative to prevent infection. In this context we investigated the role of the mammalian Chitinase-3-Like-1 (CHI3L1) non-enyzmatic protein predominately expressed on epithelial as well as innate immune cells as a potential bacterial-translocation-mediating factor. We show a strong trend that a modulation of chitinase expression is likely to be effective in reducing mortality rates in a mouse model of burn injury with superinfection with the opportunistic PA14 Pseudomonas strain, thus demonstrating possible clinical leverage.Publication Prediction of Scar Size in Rats Six Months after Burns Based on Early Post-injury Polarization-Sensitive Optical Frequency Domain Imaging(Frontiers Media S.A., 2017) Kravez, Eli; Villiger, Martin; Bouma, Brett; Yarmush, Martin; Yakhini, Zohar; Golberg, AlexanderHypertrophic scars remain a major clinical problem in the rehabilitation of burn survivors and lead to physical, aesthetic, functional, psychological, and social stresses. Prediction of healing outcome and scar formation is critical for deciding on the best treatment plan. Both subjective and objective scales have been devised to assess scar severity. Whereas scales of the first type preclude cross-comparison between observers, those of the second type are based on imaging modalities that either lack the ability to image individual layers of the scar or only provide very limited fields of view. To overcome these deficiencies, this work aimed at developing a predictive model of scar formation based on polarization sensitive optical frequency domain imaging (PS-OFDI), which offers comprehensive subsurface imaging. We report on a linear regression model that predicts the size of a scar 6 months after third-degree burn injuries in rats based on early post-injury PS-OFDI and measurements of scar area. When predicting the scar area at month 6 based on the homogeneity and the degree of polarization (DOP), which are signatures derived from the PS-OFDI signal, together with the scar area measured at months 2 and 3, we achieved predictions with a Pearson coefficient of 0.57 (p < 10−4) and a Spearman coefficient of 0.66 (p < 10−5), which were significant in comparison to prediction models trained on randomly shuffled data. As the model in this study was developed on the rat burn model, the methodology can be used in larger studies that are more relevant to humans; however, the actual model inferred herein is not translatable. Nevertheless, our analysis and modeling methodology can be extended to perform larger wound healing studies in different contexts. This study opens new possibilities for quantitative and objective assessment of scar severity that could help to determine the optimal course of therapy.