@article{
doi:10.1073/pnas.2220132120,
author = {Michael Schmalz  and Xiao-Xuan Liang  and Ines Wieser  and Caroline Gruschel  and Lukas Muskalla  and Martin Thomas Stöckl  and Roland Nitschke  and Norbert Linz  and Alfred Leitenstorfer  and Alfred Vogel  and Elisa Ferrando-May },
title = {Dissection of DNA damage and repair pathways in live cells by femtosecond laser microirradiation and free-electron modeling},
journal = {Proceedings of the National Academy of Sciences},
volume = {120},
number = {25},
pages = {e2220132120},
year = {2023},
doi = {10.1073/pnas.2220132120},
URL = {https://www.pnas.org/doi/abs/10.1073/pnas.2220132120},
eprint = {https://www.pnas.org/doi/pdf/10.1073/pnas.2220132120},
abstract = {Understanding and predicting the outcome of the interaction of light with DNA has a significant impact on the study of DNA repair and radiotherapy. We report on a combination of femtosecond pulsed laser microirradiation at different wavelengths, quantitative imaging, and numerical modeling that yields a comprehensive picture of photon-mediated and free-electron-mediated DNA damage pathways in live cells. Laser irradiation was performed under highly standardized conditions at four wavelengths between 515 nm and 1,030 nm, enabling to study two-photon photochemical and free-electron-mediated DNA damage in situ. We quantitatively assessed cyclobutane pyrimidine dimer (CPD) and γH2AX-specific immunofluorescence signals to calibrate the damage threshold dose at these wavelengths and performed a comparative analysis of the recruitment of DNA repair factors xeroderma pigmentosum complementation group C (XPC) and Nijmegen breakage syndrome 1 (Nbs1). Our results show that two-photon-induced photochemical CPD generation dominates at 515 nm, while electron-mediated damage dominates at wavelengths ≥620 nm. The recruitment analysis revealed a cross talk between nucleotide excision and homologous recombination DNA repair pathways at 515 nm. Numerical simulations predicted electron densities and electron energy spectra, which govern the yield functions of a variety of direct electron-mediated DNA damage pathways and of indirect damage by •OH radicals resulting from laser and electron interactions with water. Combining these data with information on free electron–DNA interactions gained in artificial systems, we provide a conceptual framework for the interpretation of the wavelength dependence of laser-induced DNA damage that may guide the selection of irradiation parameters in studies and applications that require the selective induction of DNA lesions.}}

@Inbook{Linz2023,
author="Linz, Norbert
and Freidank, Sebastian
and Liang, Xiao-Xuan
and Vogel, Alfred",
editor="Stoian, Razvan
and Bonse, J{\"o}rn",
title="Laser Micro- and Nanostructuring for Refractive Eye Surgery",
bookTitle="Ultrafast Laser Nanostructuring: The Pursuit of Extreme Scales",
year="2023",
publisher="Springer International Publishing",
address="Cham",
pages="1217--1245",
abstract="Every year, more than a million refractive eye operations using femtosecond (fs) laser procedures are performed, and yet the cutting process in corneal tissue remains an area for development. In this chapter, we first review the state of the art of infrared (IR) fs laser dissection in laser in situ keratomileusis (LASIK) and small incision lenticule extraction (SMILE) and formulate the challenges for an improvement of precision and reduction of side effects. Since overcoming these challenges requires better knowledge of the cutting mechanisms, the plasma-mediated corneal dissection process is analyzed by high-speed photography of laser-induced bubble dynamics with up to 50 Mio frames/s, histological analysis of the cuts, and gas chromatography of the dissection products. Based on these results, we show that cutting efficiency and precision are improved through focus shaping by means of a helical phase plate, which converts the linear polarized Gaussian fs laser beam into a Laguerre-Gaussian vortex beam. The focus of the vortex beam has a ring shape with the same length in axial direction as the focus of a Gaussian beam but larger diameter. This greatly facilitates cleavage along the corneal lamellae, enabling cutting with low plasma energy density, higher precision, and fewer mechanical side effects. A shortening of the laser plasma length at constant focusing angle by use of UV-A laser pulses instead of IR pulses further improves precision. To compare the performance of UV and IR Gaussian and vortex beams, the incident and absorbed laser energy needed for easy removal of flaps created in porcine corneas are determined at various pulse durations and the smoothness of cuts is evaluated by scanning electron microscopy. Overall, vortex beams perform better than Gaussian beams for all wavelengths and can be easily implemented in clinical systems. Finally, we discuss a novel concept for refractive correction based on the introduction of refractive index changes in the corneal stroma by localized low-density plasma formation. Experimental findings that UV wavelengths work better for this purpose than IR wavelengths are explained through an analysis of the wavelength dependence of free electron density and energy spectrum that are obtained by numerical simulations.",
isbn="978-3-031-14752-4",
doi="10.1007/978-3-031-14752-4_33",
url="https://doi.org/10.1007/978-3-031-14752-4_33"
}

@article{Liang2022,
   author = {Liang, X-X;Linz, N;Freidank, S;Paltauf, G and Vogel, A},
   title = {Comprehensive analysis of spherical bubble oscillations and shock wave emission in laser-induced cavitation},
keywords = {bubble dynamics, cavitation, shock waves},
   journal = {Journal of Fluid Mechanics},
   volume = {940},
   pages = {A5},
   ISSN = {0022-1120},
   DOI = {10.1017/jfm.2022.202},
  
   year = {2022},
   type = {Journal Article}
}

@article{Freidank2022,
   author = {Freidank, S;Vogel, A and Linz, N},
   title = {Mechanisms of corneal intrastromal laser dissection for refractive surgery: ultra-high-speed photographic investigation at up to 50 million frames per second},
   journal = {BioOptExpr},
   volume = {13 (5)},
   
   pages = {3056-3079},
   DOI = {10.1364/BOE.455926},

   year = {2022},
   type = {Journal Article}
}

@inproceedings{Linz2021,
   author = {Ibey, B L and Linz, N},
   title = {Front Matter: Volume 11640},
   booktitle = {SPIE BiOS},
Year = {2021},
   publisher = {SPIE},
   volume = {11640},
   url = {https://doi.org/10.1117/12.2596605},
   type = {Conference Proceedings}
}

@article{Freidank2020,
   author = {Freidank, S;Vogel, A and Linz, N},
   title = {Optical Vortex Beam for Gentle and Ultraprecise Intrastromal Corneal Dissection in Refractive Surgery},
   journal = {TVST},
   volume = {9(10)},
   
   pages = {22-22},
   ISSN = {2164-2591},
 
   url = {https://doi.org/10.1167/tvst.9.10.22},
   year = {2020},
   type = {Journal Article}
}

@inproceedings{Linz2020,
   author = {Ibey, B L and Linz, N},
   title = {Optical Interactions with Tissue and Cells XXXI},
   booktitle = {Proc. of SPIE Vol},
   volume = {11238},
   pages = {1123801-1},
year = {2020},
   ISBN = {ISBN: 9781510632394},
   DOI = {10.1117/12.2569811},
   type = {Conference Proceedings}
}

@article{Freidank2019,
   author = {Freidank, S;Vogel, A;Anderson, R. R.;Birngruber, R and Linz, N},
   title = {Correction of hyperopia by intrastromal cutting and liquid filler injection},
   journal = {J Biomed Opt},
  
   number = {5%J Journal of Biomedical Optics},
   pages = {1-7, 7},
   
   url = {https://doi.org/10.1117/1.JBO.24.5.058001},
   year = {2019},
   type = {Journal Article}
}

@article{Linz2016,
   author = {Linz, Norbert and Freidank, Sebastian and Liang, Xiao-Xuan and Vogel, Alfred},
   title = {Wavelength dependence of femtosecond laser-induced breakdown in water and implications for laser surgery},
   journal = {American Physical Society,Phys. Rev. B},
   volume = { 94},
   number = {2},
   pages = {1-19},
   url = {http://link.aps.org/doi/10.1103/PhysRevB.94.024113},
   year = {2016},
   type = {Journal Article}
}

@article{Linz2015,
   author = {Linz, Norbert and Freidank, Sebastian and Liang, Xiao-Xuan and Vogelmann, Hannes and Trickl, Thomas and Vogel, Alfred},
   title = {Wavelength dependence of nanosecond infrared laser-induced breakdown in water: Evidence for multiphoton initiation via an intermediate state},
   journal = {Physical Review B},
   volume = {91},
   number = {13},
   pages = {134114},
   note = {PRB},
   DOI = {doi/10.1103/PhysRevB.91.134114},
   url = {http://link.aps.org/doi/10.1103/PhysRevB.91.134114},
   year = {2015},
   type = {Journal Article}
}

@article{Vogel2014,
   author = {Vogel, A and Freidank, S and Linz, N },
   title = {Alternativen zur Femtosekundentechnologie: UV Subnanosekunden-pulse und Ringfoki für LASIK Flaperzeugung (at press)},
   journal = {Ophthalomologe },
   volume = {111},
   number = {6},
   year = {2014},
   type = {Journal Article}
}

@article{Trost2013,
   author = {Trost, Andrea and Schroedl, Falk and Strohmaier, Clemens A and Bogner, Barbara and Runge, Christian and Kaser-Eichberger, Alexandra and Krefft, Karolina Anna and Vogel, Alfred and Linz, Norbert and Freidank, Sebastian and Hilpert, Andrea and Zimmermann, Inge and Grabner, Günther and Reitsamer, Herbert A},
   title = {A new nanosecond UV-laser at 355 nm: early results of corneal flap cutting in a rabbit model},
   journal = {Investigative Ophthalmology & Visual Science},
   abstract = {Purpose: A new 355nm UV laser was used for corneal flap cutting in an animal model and tested for clinical and morphological alterations. Methods: Corneal flaps were created (Chinchilla Bastards; n=25) with an UV-nanosecond laser at 355nm (150kHz, pulse duration 850ps, spot-size 1µm, spot-spacing 6x6µm, side-cut Δz 1µm; cutting depth 130µm) and pulse energies of 2.2 or 2.5µJ, respectively. Following slit lamp examination, animals were sacrificed at 6, 12 and 24hrs after treatment. Corneas were prepared for histology (HE, TUNEL-assay) and evaluated statistically, followed by ultrastructural investigations. Results: Laser treatment was tolerated well, flap lift was easier at 2.5µJ compared to 2.2µJ. Standard HE at 24hrs revealed intact epithelium in the horizontal cut, with similar increase in corneal thickness at both energies. Irrespective of energy levels, TUNEL assay revealed comparable numbers of apoptotic cells in the horizontal and vertical cut at 6/12/24hrs, becoming detectable in the horizontal cut as an acellular stromal band at 24hrs. Ultrastructural analysis revealed regular morphology in the epi- and endothelium, while in the stroma, disorganized collagen lamellae were detectable representing the horizontal cut, again irrespective of energy levels applied. Conclusions:This new UV-laser revealed no epithelial nor endothelial damage at energies feasible for corneal flap cutting. Observed corneal swelling was lower compared to existing UV-lasers-studies, albeit total energy applied here was much higher. Observed loss of stromal keratinocytes is comparable to available laser systems. Therefore, this new laser is suitable for refractive surgery, awaiting its test in a chronic environment.},
   DOI = {10.1167/iovs.13-12580},
   url = {http://www.iovs.org/content/early/2013/10/28/iovs.13-12580.abstract},
   year = {2013},
   type = {Journal Article}
}

@article{Freidank,
   author = {Freidank, S. and Linz, N.},
   title = {Mit der biomedizinischen Optik hoch hinaus - Lübecker Projekt zur Laserforschung auf der Zugspitze },
   journal = {Focus Uni Luebeck / Universität Lübeck},
   volume = {26},
   number = {1},
   pages = {16},
   year = {2009}
}

@misc{Vogel2008,
   author = {Vogel, A. and Linz, N. and Freidank, S. and Paltauf, G.},
   title = {Femtosecond-laser-induced nanocavitation in water: implications for optical breakdown threshold and cell surgery},
   volume = {100},
   number = {3},
   pages = {23},
   note = {Using Smart Source Parsing
Jan 25;:038102. Epub 2008 Jan},
   abstract = {We determined the bubble radius R_(max) for femtosecond optical breakdown in water at 347, 520, and 1040 nm with an unprecedented accuracy (+/-10 nm). At threshold, R_(max) was smaller than the diffraction-limited focus radius and ranged from 190 nm to 320 nm. The increase of R_(max) with laser energy E_(L) is slowest at 347 nm, providing optimum control of cell surgery. Experimental results agree with a model of bubble formation in heated and thermoelastically stretched liquids. Theory predicts a threshold temperature T_(th) approximately equal to 168 degrees C. For T>300 degrees C, a phase explosion sets in, and R_(max) increases rapidly with E_(L).},
   ISBN = {0031-9007 (Print)
0031-9007 (Linking)},
   year = {2008}
}

@article{Horneffer,
   author = {Horneffer, V. and Linz, N. and Vogel, A.},
   title = {Principles of laser-induced separation and transport of living cells},
   journal = {J Biomed Opt},
   volume = {12},
   number = {5},
   pages = {054016},
   note = {Horneffer, Verena
Linz, Norbert
Vogel, Alfred
Evaluation Studies
Research Support, Non-U.S. Gov't
United States
J Biomed Opt. 2007 Sep-Oct;12(5):054016.},
   abstract = {Separation and transport of defined populations of living cells grown on a thin membrane can be achieved by laser microdissection (LMD) of the sample of interest, followed by a laser-induced forward transport process [laser pressure "catapulting" (LPC)] of the dissected cell cluster. We investigate the dynamics of LMD and LPC with focused and defocused UV-A laser pulses by means of time-resolved photography. Catapulting is driven by plasma formation when tightly focused pulses are used, and by confined thermal ablation at the bottom of the sample for defocused catapulting. With both modalities, the initial specimen velocity amounts to about 50 to 60 ms. Time-resolved photography of live cell catapulting reveals that in defocused catapulting, strong shear forces arise when the sample is accelerated out of the culture medium covering the cells. By contrast, pulses focused at the periphery of the specimen cause a fast rotational movement that minimizes the flow of culture medium parallel to the sample surface, and thus the resulting shear stresses. Therefore, the recultivation rate of catapulted cells is much higher when focused pulses are used. Compared to collateral damage by mechanical forces, side effects by heat and UV exposure of the cells play only a minor role.},
   keywords = {Animals
CHO Cells
Cell Separation/ methods
Cricetinae
Cricetulus
Microdissection/ methods
Optical Tweezers
Specimen Handling/ methods},
   year = {2007}
}

@inbook{Vogel2007-5,
   author = {Vogel, A. and Noack, J. and Hüttmann, G. and Linz, N. and Freidank, S. and Paltauf, G.},
   title = {Chapter 18 Femtosecond laser nanosurgery of biological cells and tissues},
   booktitle = {Handai Nanophotonics},
   editor = {Hiroshi Masuhara, Satoshi Kawata and Fumio, Tokunaga},
   publisher = {Elsevier},
   volume = {Volume 3},
   pages = {273-286},
   year = { 2007}
}

@inbook{Vogel2007-4,
   author = {Vogel, A and Horneffer, V. and Lorenz, B. and Linz, N. and Freidank, S. and Hüttmann, G. and Gebert, A.},
   title = {Principles of laser microdissection and catapulting of histologic specimens and live cells},
   booktitle = {Laser Manipulation of Cells and Tissues, Methods in Cell Biology},
   editor = {Berns, M.  and Greulich, K.O.},
   publisher = {Academic Press Elsevier},
   address = {San Diego},
   volume = {82},
   pages = {153-205},
   year = { 2007}
}

@inproceedings{Vogel-2006,
   author = {Vogel, A. and Noack, J. and Hüttmann, G. and Linz, N. and Freidank, S. and Paltauf, G.},
   title = {Femtosecond laser nanosurgery of biological cells and tissues},
   booktitle = {4th International Congress on Laser Advanced Materials Processing},
Year = { 2006},
URL = { http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.713.4169&rep=rep1&type=pdf}
}