Refine
Is part of the Bibliography
- yes (614) (remove)
Year of publication
- 2019 (614) (remove)
Document Type
- Journal article (427)
- Doctoral Thesis (163)
- Preprint (19)
- Book article / Book chapter (1)
- Conference Proceeding (1)
- Other (1)
- Report (1)
- Working Paper (1)
Language
- English (614) (remove)
Keywords
- boron (11)
- apoptosis (8)
- Tissue Engineering (6)
- inflammation (6)
- ischemic stroke (6)
- cancer (5)
- measles virus (5)
- DNA methylation (4)
- Drosophila melanogaster (4)
- Hydrogel (4)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (88)
- Graduate School of Life Sciences (51)
- Physikalisches Institut (38)
- Institut für Psychologie (28)
- Institut für Anorganische Chemie (27)
- Institut für Organische Chemie (27)
- Medizinische Klinik und Poliklinik II (24)
- Neurologische Klinik und Poliklinik (24)
- Institut für Geographie und Geologie (20)
- Abteilung für Funktionswerkstoffe der Medizin und der Zahnheilkunde (18)
- Institut für Pharmazie und Lebensmittelchemie (18)
- Medizinische Klinik und Poliklinik I (18)
- Rudolf-Virchow-Zentrum (18)
- Institut für Informatik (17)
- Institut für Hygiene und Mikrobiologie (16)
- Institut für Physikalische und Theoretische Chemie (16)
- Institut für Theoretische Physik und Astrophysik (16)
- Kinderklinik und Poliklinik (15)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (15)
- Lehrstuhl für Tissue Engineering und Regenerative Medizin (15)
- Institut für Virologie und Immunbiologie (14)
- Julius-von-Sachs-Institut für Biowissenschaften (14)
- Pathologisches Institut (14)
- Institut für Klinische Epidemiologie und Biometrie (12)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (11)
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (11)
- Klinik und Poliklinik für Nuklearmedizin (11)
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie (9)
- Institut für Funktionsmaterialien und Biofabrikation (8)
- Institut für Humangenetik (8)
- Institut für Klinische Neurobiologie (8)
- Institut für Mathematik (8)
- Institut für Molekulare Infektionsbiologie (8)
- Neurochirurgische Klinik und Poliklinik (8)
- Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II) (7)
- Betriebswirtschaftliches Institut (7)
- Institut Mensch - Computer - Medien (7)
- Klinik und Poliklinik für Strahlentherapie (7)
- Klinik und Poliklinik für Unfall-, Hand-, Plastische und Wiederherstellungschirurgie (Chirurgische Klinik II) (7)
- Lehrstuhl für Orthopädie (7)
- Institut für diagnostische und interventionelle Radiologie (Institut für Röntgendiagnostik) (6)
- Institut für Experimentelle Biomedizin (5)
- Institut für Pharmakologie und Toxikologie (5)
- Fakultät für Biologie (4)
- Graduate School of Science and Technology (4)
- Institut für Anatomie und Zellbiologie (4)
- Institut für Sportwissenschaft (4)
- Institut für diagnostische und interventionelle Neuroradiologie (ehem. Abteilung für Neuroradiologie) (4)
- Klinik und Poliklinik für Anästhesiologie (ab 2004) (4)
- Klinik und Poliklinik für Hals-, Nasen- und Ohrenkrankheiten, plastische und ästhetische Operationen (4)
- Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie (4)
- Medizinische Fakultät (4)
- Volkswirtschaftliches Institut (4)
- Augenklinik und Poliklinik (3)
- Comprehensive Cancer Center Mainfranken (3)
- Klinik und Poliklinik für Mund-, Kiefer- und Plastische Gesichtschirurgie (3)
- Lehrstuhl für Biochemie (3)
- Frauenklinik und Poliklinik (2)
- Institut für Politikwissenschaft und Soziologie (2)
- Institut für Psychotherapie und Medizinische Psychologie (2)
- Institut für deutsche Philologie (2)
- Klinik und Poliklinik für Thorax-, Herz- u. Thorakale Gefäßchirurgie (2)
- Poliklinik für Zahnerhaltung und Parodontologie (2)
- Urologische Klinik und Poliklinik (2)
- Abteilung für Forensische Psychiatrie (1)
- Center for Computational and Theoretical Biology (1)
- Institut für Allgemeinmedizin (1)
- Institut für Kulturwissenschaften Ost- und Südasiens (1)
- Institut für Medizinische Strahlenkunde und Zellforschung (1)
- Institut für Philosophie (1)
- Institut für Sonderpädagogik (1)
- Institut für Systemimmunologie (1)
- Lehrstuhl für Molekulare Psychiatrie (1)
- Neuphilologisches Institut - Moderne Fremdsprachen (1)
- Physiologisches Institut (1)
- Sportzentrum (1)
Schriftenreihe
Sonstige beteiligte Institutionen
- Johns Hopkins School of Medicine (2)
- VolkswagenStiftung (2)
- Bio-Imaging Center Würzburg (1)
- CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - the development agency of the Brazilian Federal Government (1)
- Center for Nanosystems Chemistry (CNC), Universität Würzburg (1)
- DAAD - Deutscher Akademischer Austauschdienst (1)
- Department of Hematology and Oncology, Sana Hospital Hof, Hof, Germany (1)
- Department of Laboratory Medicine and Medicine Huddinge, Karolinska Institutet and University Hospital, Stockholm, Sweden (1)
- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
- Ernst Strüngmann Institute for Neuroscience in Cooperation with Max Planck Society (ESI) (1)
ResearcherID
- B-4606-2017 (1)
The aim of the work was the development of thiol-ene cross-linked hydrogels based on functionalized poly(glycidol)s (PG) and hyaluronic acid (HA) for extrusion based 3D bioprinting. Additionally, the functionalization of the synthesized PG with peptides and the suitability of these polymers for physically cross-linked gels were investigated, in a proof of principle study in order to demonstrate the versatile use of PG polymers in hydrogel development.
First, the precursor polymers of the different hydrogel systems were synthesized. For thiol-ene cross-linked hydogels, linear allyl-functionalized PG (P(AGE-co-G)) and three different thiol-(SH-)functionalized polymers, ester-containing PG-SH (PG SHec), ester-free PG-SH (PG-SHef) and HA-SH were synthesized and analysed, The degree of functionalization of these polymers was adjustable.
For physically cross-linked hydrogels, peptide-functionalized PG (P(peptide-co-G)), was synthesized through polymer analogue thiol-ene modification of P(AGE-co-G).
Subsequently, thiol-ene cross-linked hydrogels were prepared with the synthesized thiol- and allyl-functionalized polymers. Depending on the origin of the used polymers, two different systems were obtained: on the one hand synthetic hydrogels consisting of PG-SHec/ef and P(AGE-co-G) and on the other hand hybrid gels, consisting of HA-SH and P(AGE-co-G). In synthetic gels, the degradability of the gels was determined by the applied PG-SH. The use of PG-SHec resulted in hydrolytically degradable hydrogels, whereas the cross-linking with PG-SHef resulted in non-degradable gels.
The physical properties of these different hydrogel systems were determined by swelling, mechanical and diffusion studies and subsequently compared among each other. In swelling studies the differences of degradable and non-degradable synthetic hydrogels as well as the differences of synthetic compared to hybrid hydrogels were demonstrated.
Next, the stiffness and the swelling ratios (SR) of the established hydrogel systems were examined in dependency of different parameters, such as incubation time, polymer concentration and UV irradiation. In general, these measurements revealed the same trends for synthetic and hybrid hydrogels: an increased polymer concentration as well as prolonged UV irradiation led to an increased network density. Moreover, it was demonstrated that the incorporation of additional non-bound HMW HA hampered the hydrogel cross-linking resulting in gels with decreased stiffness and increased SR. This effect was strongly dependent on the amount of additional HMW HA.
The diffusion of different molecular weight fluorescein isothiocyanate-dextran (FITC-dextran) through hybrid hydrogels (with/without HMW HA) gave information about the mesh size of these gels. The smallest FITC-dextran (4 kDa) completely diffused through both hydrogel systems within the first week, whereas only 55 % of 40 kDa and 5-10 % HMW FITC-dextrans (500 kDa and 2 MDa) could diffuse through the networks.
The applicability of synthetic and hybrid hydrogels for cartilage regeneration purpose was investigated through by biological examinations. It was proven that both gels support the survival of embedded human mesenchymal stromal cells (hMSCs) (21/28 d in vitro culture), however, the chondrogenic differentiation was significantly improved in hybrid hydrogels compared to synthetic gels. The addition of non-bound HMW HA resulted in a slightly less distinct chondrogenesis.
Lastly the printability of the established hydrogel systems was examined. Therefore, the viscoelastic properties of the hydrogel solutions were adjusted by incorporation of non-bound HMW HA. Both systems could be successfully printed with high resolution and high shape fidelity.
The introduction of the double printing approach with reinforcing PCL allowed printing of hydrogel solutions with lower viscosities. As a consequence, the amount of additional HMW HA necessary for printing could be reduced allowing successful printing of hybrid hydrogel solutions with embedded cells. It was demonstrated that the integrated cells survived the printing process with high viability measured after 21 d. Moreover, by this reinforcing technique, robust hydrogel-containing constructs were fabricated.
In addition to thiol-ene cross-linked hydrogels, hydrogel cross-linking via ionic interactions was investigated with a hybrid hydrogel based on HMW HA and peptide-functionalized PG. Rheological measurements revealed an increase in the viscosity of a 2 wt.% HMW HA solution by the addition of peptide-functionalized PG. The increase in viscosity could be attributed to the ionic interactions between the positively charge PG and the negatively charge HMW HA.
In conclusion, throughout this thesis thiol-ene chemistry and PG were introduced as promising cross-linking reaction and polymer precursor for the field of biofabrication. Furthermore, the differences of hybrid and synthetic hydrogels as well as chemically and physically cross-linked hydrogels were demonstrated.
Moreover, the double printing approach was demonstrated to be a promising tool for the fabrication of robust hydrogel-containing constructs. It opens the possibility of printing hydrogels that were not printable yet, due to too low viscosities.
The Software Defined Networking (SDN) paradigm offers network operators numerous improvements in terms of flexibility, scalability, as well as cost efficiency and vendor independence. However, in order to maximize the benefit from these features, several new challenges in areas such as management and orchestration need to be addressed. This dissertation makes contributions towards three key topics from these areas.
Firstly, we design, implement, and evaluate two multi-objective heuristics for the SDN controller placement problem. Secondly, we develop and apply mechanisms for automated decision making based on the Pareto frontiers that are returned by the multi-objective optimizers. Finally, we investigate and quantify the performance benefits for the SDN control plane that can be achieved by integrating information from external entities such as Network Management Systems (NMSs) into the control loop. Our evaluation results demonstrate the impact of optimizing various parameters of softwarized networks at different levels and are used to derive guidelines for an efficient operation.
Functionalization of cells, extracellular matrix components and proteins for therapeutic application
(2019)
Glycosylation is a biochemical process leading to the formation of glycoconjugates by linking glycans (carbohydrates) to proteins, lipids and various small molecules. The glycans are formed by one or more monosaccharides that are covalently attached, thus offering a broad variety depending on their composition, site of glycan linkage, length and ramification. This special nature provides an exceptional and fine tunable possibility in fields of information transfer, recognition, stability and pharmacokinetic. Due to their intra- and extracellular omnipresence, glycans fulfill an essential role in the regulation of different endogenous processes (e.g. hormone action, immune surveillance, inflammatory response) and act as a key element for maintenance of homeostasis. The strategy of metabolic glycoengineering enables the integration of structural similar but chemically modified monosaccharide building blocks into the natural given glycosylation pathways, thereby anchoring them in the carbohydrate architecture of de novo synthesized glycoconjugates. The available unnatural sugar molecules which are similar to endogenous sugar molecules show minimal perturbation in cell function and - based on their multitude functional groups - offer the potential of side directed coupling with a target substance/structure as well as the development of new biological properties. The chemical-enzymatic strategy of glycoengineering provides a valuable complement to genetic approaches.
This thesis primarily focuses on potential fields of application for glycoengineering and its further use in clinic and research. The last section of this work outlines a genetic approach, using special Escherichia coli systems, to integrate chemically tunable amino acids into the biosynthetic pathway of proteins, enabling specific and site-directed coupling with target substances. With the genetic information of the methanogen archaea, Methanosarcina barkeri, the E. coli. system is able to insert a further amino acid, the pyrrolysine, at the ribosomal site during translation of the protein. The natural stop-codon UAG (amber codon) is used for this newly obtained proteinogenic amino acid.
Chapter I describes two systems for the integration of chemically tunable monosaccharides and presents methods for characterizing these systems. Moreover, it gives a general overview of the structure as well as intended use of glycans and illustrates different glycosylation pathways. Furthermore, the strategy of metabolic glycoengineering is demonstrated. In this context, the structure of basic building blocks and the epimerization of monosaccharides during their metabolic fate are discussed.
Chapter II translates the concept of metabolic glycoengineering to the extracellular network produced by fibroblasts. The incorporation of chemically modified sugar components in the matrix provides an innovative, elegant and biocompatible method for site-directed coupling of target substances. Resident cells, which are involved in the de novo synthesis of matrices, as well as isolated matrices were characterized and compared to unmodified resident cells and matrices. The natural capacity of the matrix can be extended by metabolic glycoengineering and enables the selective immobilization of a variety of therapeutic substances by combining enzymatic and bioorthogonal reaction strategies. This approach expands the natural ability of extracellular matrix (ECM), like the storage of specific growth factors and the recruitment of surface receptors along with synergistic effects of bound substances. By the selection of the cell type, the production of a wide range of different matrices is possible.
Chapter III focuses on the target-oriented modification of cell surface membranes of living fibroblast and human embryonic kidney cells. Chemically modified monosaccharides are inserted by means of metabolic glycoengineering and are then presented on the cell surface. These monosaccharides can later be covalently coupled, by “strain promoted azide-alkyne cycloaddition“ (SPAAC) and/or “copper(I)-catalyzed azide-alkyne cycloaddition“ (CuAAC), to the target substance. Due to the toxicity of the copper catalysator in the CuAAC, cytotoxicity analyses were conducted to determine the in vivo tolerable range for the use of CuAAC on living cell systems. Finally, the efficacy of both bioorthogonal reactions was compared.
Chapter IV outlines two versatile carrier – spacer – payload delivery systems based on an enzymatic cleavable linker, triggered by disease associated protease. In the selection of carrier systems (i) polyethylene glycol (PEG), a well-studied, Food and Drug Administration approved substance and very common tool to increase the pharmacokinetic properties of therapeutic agents, was chosen as a carrier for non-targeting systems and (ii) Revacept, a human glycoprotein VI antibody, was chosen as a carrier for targeting systems. The protease sensitive cleavable linker was genetically inserted into the N-terminal region of fibroblast growth factor 2 (FGF-2) without jeopardizing protein activity. By exchanging the protease sensitive sequence or the therapeutic payload, both systems represent a promising and adaptable approach for establishing therapeutic systems with bioresponsive release, tailored to pre-existing conditions.
In summary, by site-specific functionalization of various delivery platforms, this thesis establishes an essential cornerstone for promising strategies advancing clinical application. The outlined platforms ensure high flexibility due to exchanging single or multiple elements of the system, individually tailoring them to the respective disease or target site.
Pro-migratory signals mediated by the tumor microenvironment contribute to the cancer progression cascade, including invasion, metastasis and resistance to therapy. Derived from in vitro studies, isolated molecular steps of cancer invasion programs have been identified but their integration into the tumor microenvironment and suitability as molecular targets remain elusive. The purpose of the study was to visualize central aspects of tumor progression, including proliferation, survival and invasion by real-time intravital microscopy. The specific aims were to monitor the kinetics, mode, adhesion and chemoattraction mechanisms of tumor cell invasion, the involved guidance structures, and the response of invasion zones to anti-cancer therapy. To reach deeper tumor regions by optical imaging with subcellular resolution, near-infrared and infrared excited multiphoton microscopy was combined with a modified dorsal skinfold chamber model. Implanted HT-1080 fibrosarcoma and B16/F10 and MV3 melanoma tumors developed zones of invasive growth consisting of collective invasion strands that retained cell-cell contacts and high mitotic activity while invading at velocities of up to 200 μm per day. Collective invasion occurred predominantly along preexisting tissue structures, including blood and lymph vessels, collagen fibers and muscle strands of the deep dermis, and was thereby insensitive to RNAi based knockdown and/or antibody-based treatment against β1 and β3 integrins, chemokine (SDF-1/CXCL12) and growth factor (EGF) signaling. Therapeutic hypofractionated irradiation induced partial to complete regression of the tumor main mass, yet failed to eradicate the collective invasion strands, suggesting a microenvironmentally privileged niche. Whereas no radiosensitization was achieved by interference with EGFR or doxorubicin, the simultaneous inhibition of β1 and β3 integrins impaired cell proliferation and survival in spontaneously growing tumors and strongly enhanced the radiation response up to complete eradication of both main tumor and invasion strands. In conclusion, collective invasion in vivo is a robust process which follows preexisting tissue structures and is mainly independent of established adhesion and chemoattractant signaling. Due to its altered biological response to irradiation, collective invasion strands represent a microenvironmentally controlled and clinically relevant resistance niche to therapy. Therefore supportive regimens, such as anoikisinduction by anti-integrin therapy, may serve to enhance radio- and chemoefficacy and complement classical treatment regimens.