Synthesis of an erodible biomimetic hydrogel for drug delivery using native chemical ligation

Hydrogels are hydrophilic, three dimensional polymers that imbibe large quantities of water while remaining insoluble in aqueous solutions due to chemical or physical cross-linking. The polymers swell in water or biological fluids, immobilizing the bioactive agent, leading to drug release in a well-defined specific manner. Thus the hydrogels’ elastic properties, swellability and biocompatibility make them excellent formulations for drug delivery. Currently, many drug potencies and therapeutic effects are limited or otherwise reduced because of the partial degradation that occurs before the administered drug reaches the desired site of action. On the other hand, sustained release medications release drugs continually, rather than providing relief of symptoms and protection solely when necessary. In fact, it would be much better if drugs could be administered in a manner that precisely matches physiological needs at desired times and at the desired site (site specific targeting). There is therefore an unmet need to develop controlled drug delivery systems especially for delivery of peptide and protein bound drugs. The purpose of this project is to produce hydrogels for structural drug delivery and time-dependent sustained release of drugs (bioactive agents). We use an innovative polymerisation strategy based on native chemical ligation (NCL) to covalently cross-link polymers to form hydrogels. When mixed in aqueous solution, four armed (polyethylene glycol) amine (PEG-4A) end functionalised with thioester and four branched Nterminal cysteine peptide dendrimers spontaneously conjugated to produce biomimetic hydrogels. These hydrogels showed superior resistance to shear stress compared to an equivalent PEG macromonomer system and were shown to be proteolytically degradable with concomitant release of a model payload molecule. This is the first report of a peptide dendrimers/PEG macromonomer approach to hydrogel production and opens up the prospect of facile hydrogel synthesis together with tailored payload release.

Advanced Bioactive Inorganic Materials for Bone Regeneration and Drug Delivery

Bioceramics play an important role in repairing and regenerating bone defects. Annually, more than 500,000 bone graft procedures are performed in the United states and approximately 2.2 million are conducted worldwide. The estimated cost of these procedures approaches $2.5billion per year. Around 60% of the bone graft substitutes available on the market involve bioceramics. It is reported that bioceramics in the world market increase by 9% per year. For this reason, the research of bioceramics has been one of the most active areas during, the past several years. Considering the significant importance of bioceramics, our goal was to compile this book to review the latest research advances in the field of bioceramics. The text also summarizes our work during the past 10 years in an effort to share innovative concepts, design of bioceramisc, and methods for material synthesis and drug delivery. We anticipate that this text will provide some useful information and guidance in the bioceramics field for biomedical engineering researchers and material scientists. Information on novel mesoporous bioactive glasses and silicate-based ceramics for bone regeneration and drug delivery are presented. Mesoporous bioactive glasses have shown multifunctional characteristics of bone regeneration and drug delivery due to their special mesopore structures,whereas silicated-based bioceramics, as typical third-generation biomaterials,possess significant osteostimulation properties. Silica nanospheres with a core-shell structure and specific properties for controllable drug delivery have been carefully reviewed-a variety of advanced synthetic strategies have been developed to construct functional mesoporous silica nanoparticles with a core-shell structure, including hollow, magnetic, or luminescent, and other multifunctional core-shell mesoporous silica nanoparticles. In addition, multifunctional drug delivery systems based on these nanoparticles have been designed and optimized to deliver the drugs into the targeted organs or cells,with a controllable release fashioned by virtue of various internal and external triggers. The novel 3D-printing technique to prepare advanced bioceramic scaffolds for bone tissue engineering applications has been highlighted, including the preparation, mechanical strength, and biological properties of 3D-printed porous scaffolds of calcium phosphate cement and silicate bioceramics. Three-dimensional printing techniques offer improved large-pore structure and mechanical strength. In addition , biomimetic preparation and controllable crystal growth as well as biomineralization of bioceramics are summarized, showing the latest research progress in this area. Finally, inorganic and organic composite materials are reviewed for bone regeneration and gene delivery. Bioactive inorganic and organic composite materials offer unique biological, electrical, and mechanical properties for designing excellent bone regeneration or gene delivery systems. It is our sincere hope that this book will updated the reader as to the research progress of bioceramics and their applications in bone repair and regeneration. It will be the best reward to all the contributors of this book if their efforts herein in some way help reader in any part of their study, research, and career development.

Using Wikipedia to improve web service discovery

Building and maintaining software are not easy tasks. However, thanks to advances in web technologies, a new paradigm is emerging in software development. The Service Oriented Architecture (SOA) is a relatively new approach that helps bridge the gap between business and IT and also helps systems remain exible. However, there are still several challenges with SOA. As the number of available services grows, developers are faced with the problem of discovering the services they need. Public service repositories such as Programmable Web provide only limited search capabilities. Several mechanisms have been proposed to improve web service discovery by using semantics. However, most of these require manually tagging the services with concepts in an ontology. Adding semantic annotations is a non-trivial process that requires a certain skill-set from the annotator and also the availability of domain ontologies that include the concepts related to the topics of the service. These issues have prevented these mechanisms becoming widespread. This thesis focuses on two main problems. First, to avoid the overhead of manually adding semantics to web services, several automatic methods to include semantics in the discovery process are explored. Although experimentation with some of these strategies has been conducted in the past, the results reported in the literature are mixed. Second, Wikipedia is explored as a general-purpose ontology. The benefit of using it as an ontology is assessed by comparing these semantics-based methods to classic term-based information retrieval approaches. The contribution of this research is significant because, to the best of our knowledge, a comprehensive analysis of the impact of using Wikipedia as a source of semantics in web service discovery does not exist. The main output of this research is a web service discovery engine that implements these methods and a comprehensive analysis of the benefits and trade-offs of these semantics-based discovery approaches.

Risk-taking, harm and help-seeking : reported by young people in treatment at a youth alcohol and drug counselling service

Regarded as a normative component of development, risk-taking by young people is a well-researched subject, and some risk-taking behaviours, such as substance use, are particularly well covered because of their potential to adversely affect health and wellbeing. What has remained unclear is the extent of young people's risk-taking while engaged in alcohol and other drug (AOD) treatment, their awareness of the related harms of risk-taking behaviours, and their prior help-seeking for these harms - information which may have a significant impact on the quality and relevance of the care they receive. This paper reports the findings from a brief pilot study exploring those factors in a clinical sample of young people engaged in ongoing AOD counselling.

Mathematical modelling of controlled drug release from polymer micro-spheres : incorporating the effects of swelling, diffusion and dissolution via moving boundary problems

Controlled drug delivery is a key topic in modern pharmacotherapy, where controlled drug delivery devices are required to prolong the period of release, maintain a constant release rate, or release the drug with a predetermined release profile. In the pharmaceutical industry, the development process of a controlled drug delivery device may be facilitated enormously by the mathematical modelling of drug release mechanisms, directly decreasing the number of necessary experiments. Such mathematical modelling is difficult because several mechanisms are involved during the drug release process. The main drug release mechanisms of a controlled release device are based on the device’s physiochemical properties, and include diffusion, swelling and erosion. In this thesis, four controlled drug delivery models are investigated. These four models selectively involve the solvent penetration into the polymeric device, the swelling of the polymer, the polymer erosion and the drug diffusion out of the device but all share two common key features. The first is that the solvent penetration into the polymer causes the transition of the polymer from a glassy state into a rubbery state. The interface between the two states of the polymer is modelled as a moving boundary and the speed of this interface is governed by a kinetic law. The second feature is that drug diffusion only happens in the rubbery region of the polymer, with a nonlinear diffusion coefficient which is dependent on the concentration of solvent. These models are analysed by using both formal asymptotics and numerical computation, where front-fixing methods and the method of lines with finite difference approximations are used to solve these models numerically. This numerical scheme is conservative, accurate and easily implemented to the moving boundary problems and is thoroughly explained in Section 3.2. From the small time asymptotic analysis in Sections 5.3.1, 6.3.1 and 7.2.1, these models exhibit the non-Fickian behaviour referred to as Case II diffusion, and an initial constant rate of drug release which is appealing to the pharmaceutical industry because this indicates zeroorder release. The numerical results of the models qualitatively confirms the experimental behaviour identified in the literature. The knowledge obtained from investigating these models can help to develop more complex multi-layered drug delivery devices in order to achieve sophisticated drug release profiles. A multi-layer matrix tablet, which consists of a number of polymer layers designed to provide sustainable and constant drug release or bimodal drug release, is also discussed in this research. The moving boundary problem describing the solvent penetration into the polymer also arises in melting and freezing problems which have been modelled as the classical onephase Stefan problem. The classical one-phase Stefan problem has unrealistic singularities existed in the problem at the complete melting time. Hence we investigate the effect of including the kinetic undercooling to the melting problem and this problem is called the one-phase Stefan problem with kinetic undercooling. Interestingly we discover the unrealistic singularities existed in the classical one-phase Stefan problem at the complete melting time are regularised and also find out the small time behaviour of the one-phase Stefan problem with kinetic undercooling is different to the classical one-phase Stefan problem from the small time asymptotic analysis in Section 3.3. In the case of melting very small particles, it is known that surface tension effects are important. The effect of including the surface tension to the melting problem for nanoparticles (no kinetic undercooling) has been investigated in the past, however the one-phase Stefan problem with surface tension exhibits finite-time blow-up. Therefore we investigate the effect of including both the surface tension and kinetic undercooling to the melting problem for nanoparticles and find out the the solution continues to exist until complete melting. The investigation of including kinetic undercooling and surface tension to the melting problems reveals more insight into the regularisations of unphysical singularities in the classical one-phase Stefan problem. This investigation gives a better understanding of melting a particle, and contributes to the current body of knowledge related to melting and freezing due to heat conduction.

Understanding the operational structure of Southeast Asian drug trafficking groups in Australia

This thesis examined the operational structure of Southeast Asian drug trafficking groups operating on the eastern seaboard of Australia by testing the validity and application of organised crime and drug trafficking typologies using data obtained from 159 drug trafficking cases in three Australian states: New South Wales; Queensland; and Victoria. Key findings indicated that the usefulness of typologies is limited when classifying and analysing organised crime groups. In particular, Southeast Asian drug trafficking groups operated largely in small, informal, family-based hierarchies or groups that were better conceptualised using theoretical perspectives from network and cultural studies. The study recommended that replicating previous empirical research in the field is an effective approach that will contribute towards building a cumulative body of knowledge on organised crime structures.

Ownership, corporate governance and timeliness of price discovery : Australian evidence

This study investigates whether and how a firm’s ownership and corporate governance affect its timeliness of price discovery, which is referred to as the speed of incorporation of value-relevant information into the stock price. Using a panel data of 1,138 Australian firm-year observations from 2001 to 2008, we predict and find a non-linear relationship between ownership concentration and the timeliness of price discovery. We test the identity of the largest shareholder and find that only firms with family as the largest shareholder exhibit faster price discovery. There is no evidence that suggests that the presence of a second largest shareholder affects the timeliness of price discovery materially. Although we find a positive association between corporate governance quality and the timeliness of price discovery, as expected, there is no interaction effect between the largest shareholding and corporate governance in relation to the timeliness of price discovery. Further tests show no evidence of severe endogeneity problems in our study.

Confronting the conspiracy of silence and denial of difference for late discovery adoptive persons and donor conceived people

This article outlines the impact that a conspiracy of silence and denial of difference has had on some adopted and donor conceived persons who have been lied to or misled about their origins. Factors discussed include deceit - expressed as a central secret which undermines the fabric of a family and through distortion mystifies communication processes; the shock of discovery - often revealed accidentally and the associated sense of betrayal when this occurs; and a series of losses, for example, kinship, medical history, culture and agency which result in having to rebuild personal identity. By providing those affected with a voice, validation and vindication healing can begin. Any feelings of disregard, of betrayal of trust, of anger, frustration, sorrow or loss, need to be regarded as real, expected, and above all, a valid reaction to what has occurred. The author is a 'late discoverer' of her adoption and draws on the information from her doctoral research on the same topic which was completed in 2012.

Exploring the ethical implications of the late discovery of adoptive and donor-insemination offspring status

Some children adopted under the now discredited period of closed adoption were never told of their adoptive status until it was revealed to them in adulthood. Yet to date, this ‘late-discovery’ experience has received little research attention. Now a new generation of ‘late discoverers’ is emerging as a result of (heterosexual couple) donor insemination (DI) practices. This study of 25 late-discovery participants of either adoptive or (heterosexual couple) DI offspring status reveals ethical concerns particular to the lateness of discovery. Most of the participants were Australian, with the remainder from the UK, USA and Canada. All were asked to give an ‘open’ account of their experience, with four themes or suggestions provided on request. These accounts were added to those available in relevant publications. The analysis employed a hermeneutic phenomenological methodology and all accounts were analysed using an ethical perspective developed by Walker (2006, 2007). The main themes that emerged were: disrupted personal autonomy, betrayal of deep levels of trust and feelings of injustice and diminished self-worth. The lack of recognition of concerns particular to late discovery has resulted in late discoverers (i) feeling unable to regain a sense of personal control, (ii) significantly disrupted relationships with those closest to them and others, including community and institutions, and (iii) feelings of diminished value and self-worth.

Youth Alcohol and Drug Practice Guide 3 : Practice Strategies and Interventions

This guide canvasses a range of practice strategies and interventions utilised by workers and services who engage with young people experiencing problematic AOD use whilst also exploring the many and varied challenges associated with this type of work.

An evaluation framework for cross-lingual link discovery

Cross-Lingual Link Discovery (CLLD) is a new problem in Information Retrieval. The aim is to automatically identify meaningful and relevant hypertext links between documents in different languages. This is particularly helpful in knowledge discovery if a multi-lingual knowledge base is sparse in one language or another, or the topical coverage in each language is different; such is the case with Wikipedia. Techniques for identifying new and topically relevant cross-lingual links are a current topic of interest at NTCIR where the CrossLink task has been running since the 2011 NTCIR-9. This paper presents the evaluation framework for benchmarking algorithms for cross-lingual link discovery evaluated in the context of NTCIR-9. This framework includes topics, document collections, assessments, metrics, and a toolkit for pooling, assessment, and evaluation. The assessments are further divided into two separate sets: manual assessments performed by human assessors; and automatic assessments based on links extracted from Wikipedia itself. Using this framework we show that manual assessment is more robust than automatic assessment in the context of cross-lingual link discovery.

Overview of the NTCIR-10 cross-lingual link discovery task

This paper presents an overview of NTCIR-10 Cross-lingual Link Discovery (CrossLink-2) task. For the task, we continued using the evaluation framework developed for the NTCIR-9 CrossLink-1 task. Overall, recommended links were evaluated at two levels (file-to-file and anchor-to-file); and system performance was evaluated with metrics: LMAP, R-Prec and P@N.

Pharmacokinetic studies of a Chinese triple herbal drug formula

Yin Chen Hao Tang preparation (YCHTP) is a classic traditional Chinese medicine formula, which is commonly used for clinical treatment of hepatological diseases. In this study, a rapid and validated high-performance liquid chromatography (HPLC) method was developed to simultaneously identify 6,7-dimethylesculetin and geniposide in rat plasma. This assay was performed on a Dikma Diamonsil RP(18) column (200 mmx4.6 mm, 5 mum) with acetonitrile-methanol-water (0.1% formic acid) as the mobile phase, showing acceptable linearity, intra- and inter-day precision and accuracy (R.S.D.=5%), and absolute recovery for two analytes (74%); the limits of quantitation were 0.4 and 1.12 mug/ml, and the limits of detection were 0.06 and 0.09 mug/ml for two analytes. The developed method was successfully applied to study the effect of formula compatibility on the pharmacokinetics of 6,7-dimethylesculetin and geniposide in YCHTP when orally administrating an effective human daily dose of YCHTP to rats. We surmise that formula compatibility can significantly influence the pharmacokinetics of YCHTP, and we have elucidated and validated the compatible administration of YCHTP.

A data mining framework for relevance feature discovery

This thesis is a study for automatic discovery of text features for describing user information needs. It presents an innovative data-mining approach that discovers useful knowledge from both relevance and non-relevance feedback information. The proposed approach can largely reduce noises in discovered patterns and significantly improve the performance of text mining systems. This study provides a promising method for the study of Data Mining and Web Intelligence.