Stimulating angiogenesis into biomaterials through the delivery of growth factors

lschemic disease in form of ischemic heart disease (IHD), ischemic stroke and peripheral arterial disease (PAD) due to atherosclerosis represents a massive clinical and economic burden to healthcare and is currently the number one cause of death in the world. Treatment modalities for peripheral arterial disease include bypass surgery involving autologous vein or synthetic materials such as ePTFE. Long term patency of small diameter vascular grafts used for infra-inguinal reconstructions, however, is below 50 % 5 years after implantation. Therefore, novel vascular graft concepts and materials are needed. The concept of transmural in vivo endothelialisation of vascular grafts holds great promise for increasing long term patency. To achieve complete luminal endothelial cell coverage and optimal integration of the porous synthetic graft material into the host tissue, transmural ingrowth of tissue and vasa vasorum might have to be facilitated. Since VEGF1ss and PDGF-BB are growth factors known to stimulate and consolidate angiogenesis, this PhD thesis hypothesized, that neovascularisation of porous polyurethane (PU) can be increased by delivery of vascular endothelial growth factor (VEGF1ss) and platelet derived growth factor (PDGF-BB). To prove this hypothesis, subcutaneous implantation of PU discs was established as a valid, reproducible, relatively simple and quantifiable neovascularisation model. Three different ways of growth factor delivery were investigated. The gene encoding for human VEGF15s was cloned into the genome of adeno associated viruses (AAV), which served as a vector for gene transduction of autologous wound healing cells in vivo using the "Gene Activated Matrix" approach. Genetically modified matrix embedded AAV-VEGF155 was loaded into porous PU and transduced autologous ingrowing wound cells. In contrast to the excellent transduction efficiency in myocytes, AA V showed a poor tropism for wound healing cells. The second approach to increase neovascularisation into porous PU was the surface modification of PU by covalent attachment of nitrous acid degraded heparin. Neovascularisation into the biomaterial was increased by 77 % after 10 days of subcutaneous implantation. Since certain angiogenic growth factors show a high affinity for heparin, additional loading of heparin surface modified PU with VEGF165 increased neovascularisation even further up to 115 % at 10 days compared to control. Dual growth factor delivery of VEGF 165 and PDGF-BB not only initiated increased vascularisation of porous PU, but also created a stable vascular network 2 months after implantation. In contrast, PU loaded with VEGF165 alone showed regression of total vascular area of 61 % compared to vascular area at 10 days. Thirdly, to study the effects of controlled, prolonged growth factor delivery, a "Neovascularisation Construct" was developed which was implanted subcutaneously in rats. The construct consisted of an osmotic mini pump and a tube of porous PU lined with ePTFE, into which a defined amount of VEGF16s was pumped for 10 days. After implantation, granulation tissue was growing into the pores of the PU and neovascular area was increased up to 265 % compared to PBS control. Furthermore, using different growth factor concentration, a dose dependency was shown. In addition, this thesis investigated the functional perfusion of the micro vascular network growing into PU by four different vascular quantification techniques. lntravital perfusion with biotinylated lycopersicon esculentum followed by microscopical analysis, vascular corrosion casting quantified by scanning electron microscopy as well as the novel micro-CT analysis of silicone rubber perfused vessels were compared to conventional immunhistochemical analysis of endothelial cells by CD31. Interestingly, PBS perfused "Neovascularisation Constructs" showed a relatively poor perfusion; therefore CD31 immunohistochemistry "overestimated" functional neovascularisation 3 fold. All perfusion techniques indicated a strong effect of VEGF 165 delivery on vessel perfusion (10 to 20 fold increases of vascular area and volume compared to PBS control). Micro-CT scanning was shown to be an excellent tool to study micro vascular networks in a three-dimensional fashion across the whole length of the sample in a limited amount of time and to provide reliable and reproducible data on vessel density, vascular volume, and connectivity. Since resolution is still limited today to about 10 μm using a commercially available bench top scanner, this new technology still needs to be complemented by immunohistochemistry and perfusion studies such as lectin perfusion and corrosion casting. In summary, the induction of neovascularisation was achieved by heparin surface modification alone, which was even increased through additional delivery of growth factors into the biomaterial PU. The development of a stable micro vascular network at 2 months was achieved and the functionality was shown using four different, independent techniques including the novel micro-CT scanning of neovascularisation into biomaterials. Towards the development of an in vivo, spontaneously and transmurally endothelialising vascular graft with superior long-term patency further investigations are necessary. As an initial step, increased spontaneous neovascularisation of the possible graft material polyurethane was achieved. Future steps are clearly indicated to study the translation of increased neovascularisation of the biomaterial polyurethane towards increased endothelialisation in a vascular graft model

Efficiently Reconfiguring a Connected Swarm of Labeled Robots

When considering motion planning for a swarm of n labeled robots, we need to rearrange a given start configuration into a desired target configuration via a sequence of parallel, continuous, collision-free robot motions. The objective is to reach the new configuration in a minimum amount of time; an important constraint is to keep the swarm connected at all times. Problems of this type have been considered before, with recent notable results achieving constant stretch for not necessarily connected reconfiguration: If mapping the start configuration to the target configuration requires a maximum Manhattan distance of d, the total duration of an overall schedule can be bounded to ?(d), which is optimal up to constant factors. However, constant stretch could only be achieved if disconnected reconfiguration is allowed, or for scaled configurations (which arise by increasing all dimensions of a given object by the same multiplicative factor) of unlabeled robots. We resolve these major open problems by (1) establishing a lower bound of ?(?n) for connected, labeled reconfiguration and, most importantly, by (2) proving that for scaled arrangements, constant stretch for connected reconfiguration can be achieved. In addition, we show that (3) it is NP-hard to decide whether a makespan of 2 can be achieved, while it is possible to check in polynomial time whether a makespan of 1 can be achieved

Eindringwiderstand ökologisch bewirtschafteter Ackerböden - Einfluss von Standort und Bewirtschaftung sowie Auswirkungen auf den Ertrag von Wintergetreide

Auf 32 Ökobetrieben in Deutschland wurden von 2009 bis 2012 insgesamt 128 Felder untersucht. Ziel war es wesentliche Faktoren für den Boden-Eindringwiderstand zu identifizieren und die Beziehung zwischen Eindringwiderstands-Parametern und dem Ertrag von Wintergetreide zu prüfen. Auf ca. einem Viertel der untersuchten Felder wurden häufig stark verdichtete Bodenschichten gefunden. Korrelationsanalysen ergaben als wesentliche Faktoren eines großen Eindringwiderstands im Untergrund einen hohen Sandanteil, Flachgründigkeit von Böden, warme Temperaturen, niedrige Kleegras- und Winterfruchtanteile sowie hohe Anteile an Kartoffeln in der Fruchtfolge, große Pflugtiefen und hohe Schleppergewichte. Partielle Korrelationsanalysen ergaben negative Beziehungen zwischen mehreren Verdichtungsparametern und dem Getreideertrag. Aufgrund von Interkorrelationen mit anderen den Ertrag beeinflussenden Bodeneigenschaften war eine Quantifizierung des kausalen Einflusses nicht möglich

Assessment of continuous vaginal logger-based temperature monitoring in fever-induced gilts

The aim of this study was to identify a low risk method to induce fever in gilts and to evaluate vaginal sensors for temperature monitoring. Therefore, a rhinitis atrophicans vaccine was used to induce fever to evaluate sensors and behavioral patterns. During 11 trials, two of four animals were injected with 2 mL of the vaccine Porcilis AR-T DF (Intervet) and the other two animals were treated with 2 mL of 0.9% NaCl as controls. A temperature logger (TRIX-8, LogTag Recorders, Auckland, New Zealand) was used to continuously monitor the vaginal temperature. Additionally, rectal temperatures were measured four times daily. The water consumption, food intake and locomotion behaviors of the animals were analysed one day before treatment and during the day of the treatment. The vaccine induced fever in all gilts, which occurred approximately 5.87 h after vaccination. The vaginal logger temperatures and the rectal temperatures showed a linear correlation in 21 vaccinated gilts (r = 0.86; p<0.0001) and 22 non-vaccinated gilts (r = 0.65; P<0.0001). The vaginal logger can be continuously used to measure the core temperature. Water intake decreased (p<0.0001) in the gilts with fever, whereas food intake did not change (p = 0.9411). The vaccinated gilts spent 79±16 more minutes per day lying after the vaccination (p<0.001) in comparison to the day before the vaccination. Treatment with this vaccine provides the opportunity to induce fever over a short time period (5.13 h) and mild sickness behavior in gilts to investigate disease indicators

Theory of exciton-electron scattering in atomically thin semiconductors

The realization of mixtures of excitons and charge carriers in van-der-Waals materials presents a new frontier for the study of the many-body physics of strongly interacting Bose-Fermi mixtures. In order to derive an effective low-energy model for such systems, we develop an exact diagonalization approach based on a discrete variable representation that predicts the scattering and bound state properties of three charges in two-dimensional transition metal dichalcogenides. From the solution of the quantum mechanical three-body problem we thus obtain the bound state energies of excitons and trions within an effective mass model which are in excellent agreement with Quantum Monte Carlo predictions. The diagonalization approach also gives access to excited states of the three-body system. This allows us to predict the scattering phase shifts of electrons and excitons that serve as input for a low-energy theory of interacting mixtures of excitons and charge carriers at finite density. To this end we derive an effective exciton-electron scattering potential that is directly applicable for Quantum Monte-Carlo or diagrammatic many-body techniques. As an example, we demonstrate the approach by studying the many-body physics of exciton Fermi polarons in transition-metal dichalcogenides, and we show that finite-range corrections have a substantial impact on the optical absorption spectrum. Our approach can be applied to a plethora of many-body phenomena realizable in atomically thin semiconductors ranging from exciton localization to induced superconductivity

Efficiently Reconfiguring a Connected Swarm of Labeled Robots

When considering motion planning for a swarm of $n$ labeled robots, we need to rearrange a given start configuration into a desired target configuration via a sequence of parallel, continuous, collision-free robot motions. The objective is to reach the new configuration in a minimum amount of time; an important constraint is to keep the swarm connected at all times. Problems of this type have been considered before, with recent notable results achieving constant stretch for not necessarily connected reconfiguration: If mapping the start configuration to the target configuration requires a maximum Manhattan distance of $d$, the total duration of an overall schedule can be bounded to $\mathcal{O}(d)$, which is optimal up to constant factors. However, constant stretch could only be achieved if disconnected reconfiguration is allowed, or for scaled configurations (which arise by increasing all dimensions of a given object by the same multiplicative factor) of unlabeled robots. We resolve these major open problems by (1) establishing a lower bound of $\Omega(\sqrt{n})$ for connected, labeled reconfiguration and, most importantly, by (2) proving that for scaled arrangements, constant stretch for connected reconfiguration can be achieved. In addition, we show that (3) it is NP-hard to decide whether a makespan of 2 can be achieved, while it is possible to check in polynomial time whether a makespan of 1 can be achieved.Comment: 26 pages, 17 figures, full version of an extended abstract accepted for publication in the proceedings of the 33rd International Symposium on Algorithms and Computation (ISAAC 2022

Revision der Gattung Amphidium (Musci, Dicranaceae)

Only 3 of the 13 species so far comprised in Amphidium were retained in the genus: A lapponicum (Hedw.) Schimp., A. mougeotii (B.S.G.) Schimp. and A. tortuosum (Hornschuch) Cufodontis. Amphidium. sublapponicum (C. Müll.) Broth. is conspecific with A. lapponicum, A. cyathicarpum (Mont.) Broth., A. curvipes (C. Müll.) Broth. and A. californicum (C. Müll.) Broth. are synoymous with A. tortuosum. Amphidium brevifolium Broth., A. clastophyllum Broth. and A. papillosum Broth., all known only from the type locality, are sterile and differ vegetatively from all other species of the genus. They belong probably not to Amphidium. The types of Amphidium letestui Thér. & P. Varde, A. aloysii-sabaudiae Negri and A. remotidens (C. Müll.) Broth. could not be located.Von den 13 bisher in der Gattung Amphidium eingeschlossenen Arten konnten nur 3 mit Sicherheit als zur Gattung gehörig bestimmt werden, nämlich A. lapponicum (Hedw.) Schimp., A. mougeotii (B.S.G.) Schimp.und A.tortuosum (Hornschuch) Cufodontis. A. sublapponicum (C. Müll.) Broth. wird als Synonym von A. lapponicum, A. cyathicarpum (Mont.) Broth., A. curvipes (C. Müll.) Broth. und A. californicum (C. Müll.) Broth. werden als Synonyme von A. tortuosum angesehen. Alle übrigen Arten konnten aufgrund fehlenden Herbarmaterials oder sterilen Typusmaterials nicht einwandfrei als zu Amphidium gehörig bezeichnet werden