Loss systems in a random environment

We consider a single server system with infinite waiting room in a random environment. The service system and the environment interact in both directions. Whenever the environment enters a prespecified subset of its state space the service process is completely blocked: Service is interrupted and newly arriving customers are lost. We prove an if-and-only-if-condition for a product form steady state distribution of the joint queueing-environment process. A consequence is a strong insensitivity property for such systems. We discuss several applications, e.g. from inventory theory and reliability theory, and show that our result extends and generalizes several theorems found in the literature, e.g. of queueing-inventory processes. We investigate further classical loss systems, where due to finite waiting room loss of customers occurs. In connection with loss of customers due to blocking by the environment and service interruptions new phenomena arise. We further investigate the embedded Markov chains at departure epochs and show that the behaviour of the embedded Markov chain is often considerably different from that of the continuous time Markov process. This is different from the behaviour of the standard M/G/1, where the steady state of the embedded Markov chain and the continuous time process coincide. For exponential queueing systems we show that there is a product form equilibrium of the embedded Markov chain under rather general conditions. For systems with non-exponential service times more restrictive constraints are needed, which we prove by a counter example where the environment represents an inventory attached to an M/D/1 queue. Such integrated queueing-inventory systems are dealt with in the literature previously, and are revisited here in detail

Techniques for the Fast Simulation of Models of Highly dependable Systems

With the ever-increasing complexity and requirements of highly dependable systems, their evaluation during design and operation is becoming more crucial. Realistic models of such systems are often not amenable to analysis using conventional analytic or numerical methods. Therefore, analysts and designers turn to simulation to evaluate these models. However, accurate estimation of dependability measures of these models requires that the simulation frequently observes system failures, which are rare events in highly dependable systems. This renders ordinary Simulation impractical for evaluating such systems. To overcome this problem, simulation techniques based on importance sampling have been developed, and are very effective in certain settings. When importance sampling works well, simulation run lengths can be reduced by several orders of magnitude when estimating transient as well as steady-state dependability measures. This paper reviews some of the importance-sampling techniques that have been developed in recent years to estimate dependability measures efficiently in Markov and nonMarkov models of highly dependable system

Development and Characterization of Photocrosslinkable Hyaluronic Acid Hydrogels for Cartilage Regeneration

Damage to cartilage from general wear, disease, or injury can lead to joint pain and tissue degeneration. With its limited ability for self-repair, cartilage has become a target for tissue engineering (TE). As current treatments have yet to provide long-term functional cartilage repair, this dissertation introduces the development and use of photopolymerizable hyaluronic acid (HA) based hydrogels for TE to optimize cellular interactions and neocartilage formation. By altering hydrogel design parameters (e.g., molecular weight and macromer concentration), a wide range of hydrogel properties were obtained. These hydrogels all preserved the rounded morphology of chondrocytes, but cell viability and neocartilage formation were dependent on hydrogel design, where increased crosslinking resulted in cell death and increased macromer molecular weight yielded inhomogeneities in cell and ECM distribution within the hydrogel. These variables also influenced the formed neocartilage properties. The ability of HA hydrogels to promote neocartilage formation was also dependent on cell source and culture. The expansion of chondrocytes in 2D in vitro affected neocartilage formation in HA hydrogels after the second passage, as construct properties further decreased with continued passage. Chondrocytes from different tissue sources also behaved variably in the hydrogels; auricular chondrocytes excelled in static culture and subcutaneous culture over articular chondrocytes, while articular chondrocytes were stimulated in a mechanically loaded environment. As the use of chondrocytes for cartilage TE is limited clinically, we turned to mesenchymal stem cells (MSCs). In vitro culture of MSC-laden HA hydrogels demonstrated that these HA hydrogels not only supported, but enhanced chondrogenesis when compared to relatively inert hydrogels, potentially due to receptor interactions with HA. However, in these hydrogels, ECM was localized to pericellular regions. To accelerate the diffusion and distribution of ECM proteins, hydrolytically degradable HA macromers were synthesized to create a dynamic environment. When degradation complemented ECM deposition, ECM distribution and ultimately the functional maturation of the construct were improved. While this dissertation focused on material development to improve cartilage regeneration, growth factor delivery optimization and successful implementation of these hydrogels in cartilage defect models remain, towards our goal of a successful long-term repair solution to cartilage damage

Functional Emulsions via Thiol-Ene Chemistry

Polymer particles (micro to nano) with tunable functionality have emerged as a promising and viable technology platform for applications including coatings, cosmetics, nanomedicine, and imaging. Unfortunately, the lengthy polymerization time and lack of intrinsic functionality in the monomers used to fabricate particles is an industrial challenge. Thiol-ene chemistry cirmcumvents these limitations with very rapid polymerization kinetics, high reaction yields, with supressed side reactions and inherent functionality. This dissertation demonstrates the utility of thiol-ene/yne polymerization in miniemulsion and microfluidics to generate functional materials in a one-pot-method. The functionality is typically generated via off-stoichiometry thiol-ene (OSTE) resins which allow for either excess SH or alkene/yne functionality to be present throughout the material. The accessability of these functional groups are proven via infrared spectroscopy, confocal and optical microscopy. The first chapter focuses on the burgeoning field of thiol-ene/yne chemistry within multiphase emulsions and introduces innovative methods to generate functional particles/materials. Chapter II describes the first thiol-ene miniemulsion process where surfactant concentration, ultrasonication time/amplitude, and OSTE resins are explored. Chapter III expands the miniemulsion process to include thiol-yne resins in addition to the ability to encapsulate hydrophobic materials such as modified silver nanoparticles. Chapter IV highlights the utility of thiol-ene resins within microfluidics to generate unique multiphase particles that can outperform traditional acrylate-based resins. The application of thiol-ene chemistry in emulsions introduces a new class of functional materials which can be easily translated into exicisting technologies

A bibliography on formal methods for system specification, design and validation

Literature on the specification, design, verification, testing, and evaluation of avionics systems was surveyed, providing 655 citations. Journal papers, conference papers, and technical reports are included. Manual and computer-based methods were employed. Keywords used in the online search are listed

Synthesis and Characterisation of Degradable Thermosetting Materials

Abstract Traditional thermosetting materials generally display good durability, yet poor tractability, reworkability, and degradability. This project, however, provides a class of thermoset ring-opening metathesis polymerization (ROMP) materials based on norbornene dicarboximide moieties containing acetal ester group linkage which is degradable when subjected to heat or acidic-catalysis. In this study, acetal ester linkages were introduced into di-functional monomer by a one-step neat reaction between a functionalised imidonorbornene containing a terminal carboxylic acid group and a 1,4-butanediol divinyl ether. Each monomer and product was characterised by 1H and 13C NMR analysis, while the obtained polymers were analysised by thermogravimetric analysis (TGA), FTIR, dynamic mechanical analysis (DMA) and oven. The results of TGA indicated that the cross-linked materials started losing weight at 150℃ and the extent of the weight loss at 300℃. The IR spectra as it showed the reduction in the intensity of acetal ester band not the complete disappearance. The samples were heated in the oven at 300℃ and 250℃. The results showed the higher the DFM content of the cross-linked materials and the heating temperature and the duration of the heating. 1H NMR analysis of cross-linked sample C11, after the heating treatment in the oven at 300℃ for 2hr, indicates the partial formation of linear polymer upon heating. The cross-linked materials were also subjected to acid-catalysed hydrolysis. The samples after hydrolysis in dilute acid were completely soluble in DCM and were therefore characterised by NMR, which shows all the acetal ester linkages were broken down during hydrolysis and that cross-linked polymers changed into linear polymers. Dynamic mechanical analysis was carried out on the cross-linked polymer, linear polymer, polymer after heating, and polymer after hydrolysis, which support that the crosslinking in the polymer were breakdown during heating, but a new kind of network was formed, and the complete breakdown of actela ester linkages after hydrolysis

Price of Anarchy for Non-atomic Congestion Games with Stochastic Demands

We generalize the notions of user equilibrium and system optimum to non-atomic congestion games with stochastic demands. We establish upper bounds on the price of anarchy for three different settings of link cost functions and demand distributions, namely, (a) affine cost functions and general distributions, (b) polynomial cost functions and general positive-valued distributions, and (c) polynomial cost functions and the normal distributions. All the upper bounds are tight in some special cases, including the case of deterministic demands.Comment: 31 page

Matrix Metalloproteinase-sensitive Multistage Nanogels Promote Drug Transport in 3D Tumor Model

Physiological barriers inside of tumor tissue often result in poor interstitial penetration and heterogeneous intratumoral distribution of nanoparticle-based drug delivery systems (DDS). Novel, matrix metalloproteinase (MMP)-sensitive peptide-crosslinked nanogels (pNGs) as multistage DDS are reported with a beneficial size reduction property to promote the process of deep tissue penetration. Methods: The presented pNGs are based on a dendritic polyglycerol (dPG) scaffold crosslinked by a modified MMP-sensitive fluorogenic peptide. The crosslinker integrates degradability in response to proteases present in the tumor microenvironment. Surfactant-free, inverse nanoprecipitation is employed to prepare the nanogels using strain-promoted click chemistry. The size and crosslinking density of the pNGs are controlled by the functionalization degree of dPG with cyclooctyne groups and by the peptide crosslinker fraction. The intrinsic reporter moiety of the crosslinker was used to study the influence of pNG compositions on the degradation profile. The therapeutic drug Doxorubicin was conjugated through a pH-sensitive linkage to dPG to form a multistage DDS. The penetration behavior of the pNGs was studied using agarose matrix and multicellular tumor spheroids (MCTS). Results: Nanogel sizes were controlled in the range of 150-650 nm with narrow size distributions and varying degrees of crosslinking. The pNGs showed stability in PBS and cell media but were readily degraded in the presence of MMP-7. The crosslinking density influenced the degradation kinetic mediated by MMP-7 or cells. Stable conjugation of DOX at physiological pH and controlled drug release at acidic pH were observed. The digestions of nanogels lead to a size reduction to polymer-drug fragments which efficiently penetrated into agarose gels. Moreover, the degradable multistage pNGs demonstrated deeper penetration into MCTS as compared to their non-degradable counterparts. Thus, degradable pNGs were able to deliver their cargo and efficiently reduce the cell viability in MCTS. Conclusion: The triggered size reduction of the pNGs by enzymatic degradation can facilitate the infiltration of the nanocarrier into dense tissue, and thereby promote the delivery of its cargo