In recent years, 3D printing technologies have been adopted into the medical and pharmaceutical industry for the fabrication of personalised medicines, oral dosage forms, medical implants, medical devices, tissue engineering applications, and many more. However, the use of 3D printing, in particular the low-cost Fused Deposition Modelling (FDM) 3D printing technique, has been limited due to the limited number of biocompatible materials suitable for pharmaceutical and biomedical applications. In this study, the FDM 3D printing technique was being explored for the fabrication of pharmaceutical products as it is the most widely available and easily accessible 3D printing technology.

In order to improve the usability of FDM 3D printing for pharmaceutical and biomedical applications, the studies to fabricate several different biocompatible filaments composition that can be used for drug loading were carried out. Firstly, filaments made of several pharmaceutical grade polymers were being developed using hot-melt extrusion (HME). Three types of biocompatible polymeric filaments have been developed. They are (Polylactic Acid) PLA-based, (Hydroxypropyl Cellulose) HPC-based and (Polycaprolactone) PCL-based. These filaments were added with a plasticiser, polyethylene glycol (PEG), to improve their processability and physicochemical properties of the produced filaments so that they can used in an FDM 3D printer. The HPC-based filaments were loaded with a model drug, theophylline, that exhibits poor aqueous solubility, whereas the PCL-based filaments were loaded with a readily soluble model drug, metformin. The studies showed that the filaments were effective in sustaining the release of both drug, and the sustain release properties of the filaments can be adjusted by altering the composition of the polymers.

The studies showed that the HME technology is very compatible with FDM 3D printing as it is able to produce 3D printable filaments by mixing different polymeric materials. The filaments can also be loaded with a desired drug at a required dose to allow the 3D printing of drug delivery systems. This technique allows the fabrication of personalised drug delivery systems in-house. It can be beneficial for clinics and hospitals in remote areas as the lead times can be reduced when in-house fabrication is possible. The ability to fabricate personalised medicines at hand also means that the dose can drug release patterns can be altered for the patients at any point of time when required. Apart from that, this technique can change way medicines are transported and stored, which could potentially help save cost on transportation and inventory. In addition to medicines, the FDM 3D printing technique can also be used to produce other personalised drug delivery systems such as microneedles, braces and implants of various shapes due to the flexibility of the 3D printing process.

The other aspect of this research was on the fabrication of biomedical sensors that can potentially be integrated with the 3D printed drug delivery systems to form a smart drug delivery device. The idea of smart drug delivery device is that it is capable of continuous monitoring the health of a patient and then administer drug to the patient whenever it is required. The development of such smart medical devices has been one of the hottest interests in the biomedical sector. One of the main issues with such technologies is the high cost which has caused the technologies to be not so affordable for many people. Therefore, the studies to fabricate some simple biomedical sensors such as a temperature sensor and a glucose sensor using simple and cost-effective manufacturing technique were being explored. The fabrication techniques used are FDM 3D printing and a thin-film fabrication technique that involves deposition of material using a thermal evaporator. Low-cost manufacturing techniques were being explored in order to help reduce manufacturing cost which could help improve the affordability of such technologies. The fabricated temperature and glucose sensors exhibit great stability in performance and mechanical flexibility. The flexibility allows the sensors to be conformable to curved surfaces such as the skin. Hence, the sensors are suitable to be used as a wearable device or integrated into some other medical devices to form a smart medical device.

This thesis addresses the need for environmentally and socially responsible sources of energy. Biofuels, made from organic matter, have recently become a viable alternative to petroleum-based fossil fuel. Sugar and starch make up the majority of feedstock used in biofuel production as it is easily digested. However, the use of these feedstocks is problematic as they consume resources with negative implications. By using a bacterium able to utilise five and six carbon sugars, such as the thermophile Geobacillus thermoglucosidans, organic lignocellulosic waste material can be used as a feedstock.

The aim of this project was to investigate and utilise key genetic regulators of fermentation in G. thermoglucosidans and to construct genetic engineering tools that enable strain development for second generation biofuel production. We have focused on the redox-sensing transcriptional regulator Rex, widespread in Grampositive bacteria, which controls the major fermentation pathways in response to changes in cellular NAD+/NADH ratio. Following the identification of several members of the Rex regulon via bioinformatics analysis, ChIP-seq and qRT-PCR experiments were performed to locate genome-wide binding sites and controlled genes in G. thermoglucosidans. Initial electromobility shift assay experiments were performed to demonstrate the potential for use of Rex from Clostridium thermocellum as an orthogonal regulator. To further this research, novel in vivo synthetic regulatory switches were designed and tested with the aim of controlling gene expression in response to changes in cellular redox state. In addition, new tools for the efficient genetic engineering of G. thermoglucosidans were produced and optimised, including an E. coli-G. thermoglucosidans conjugation method for plasmid transfer and gene disruption.

Research and technological development processes increasingly entail inter-organisational collaboration for the access and integration of external complementary knowledge, especially within emergent technological innovation systems and small developing countries. Collaborative efforts aggregate capabilities of individual actors into system-level innovation capacity, fostering technological and innovation outcomes from both individual organisations and the technological system as a whole.

Significant understanding of these interactive processes has been achieved by previous research on innovation systems, inter-organisational collaboration and networks, and studies of interdisciplinary scientific research. Nevertheless, further knowledge is required on how and why organisations may differ in their ability to collaboratively exploit potential complementarities. Consequently, this thesis examines institutional and organisational factors that influence the actual extent of knowledge integration achieved by public research organisations through collaborative research endeavours, within the agri-biotechnology innovation system in Uruguay.

The research followed a mixed empirical method. Exploratory interviews with members of public R&D groups and firms were conducted in order to reach a preliminary understanding of the main forces affecting collaboration and knowledge integration. Quantitative indicators of the degree of knowledge-integration achieved by R&D groups’ collaborative links were designed and computed using data gathered through a survey of R&D group members. Indicators were also developed to statistically assess how the extent of collaborative knowledge-integration achieved by an R&D group is influenced by system-level incentive institutions, by the absorptive and relational capacities of the group, and by the compliance of the group with local scientific assessment and reward mechanisms.

This thesis makes various theoretical contributions and draws relevant policy implications. The results show that members of R&D groups may exert differing levels of influence on knowledge-integration. Specifically, postgraduate students were found to play a relevant bridging role, enhancing the ability of the group to access knowledge from complementary disciplines. The study also found consistent evidence of a negative relation between an R&D group’s compliance with local scientific incentives, and the group’s ability to collaboratively integrate complementary knowledge-assets. Therefore, formal incentive institutions are presumably affecting the exploitation of potential synergies among local knowledge resources and hence the learning and innovation capabilities and the cohesion of the entire agri-biotechnology innovation system. As a methodological contribution, this thesis develops novel indicators to assess the degree of inter-organisational complementarity that go beyond those used in previous research.

Currently, there is no effective sensing technology available to monitor the electrocardiogram(ECG) activity of the living zebrafish heart during early developmental stages. Most of the methods are based either on the use of simple visual inspections which are limited to quantifying the heart-rate or invasive methodologies which require the insertion of electrodes or heart explantation techniques, both requiring the use of expensive differential amplifiers and noise isolated environments.
In this paper we report the continuous detection of the cardiac electrical activity in embryonic zebrafish using a non-invasive approach. We present a portable and cost-effective platform based on the Sussex patented Electric Potential Sensing(EPS) technology, to monitor in vivo electrocardiogram activity from the zebrafish heart. We present results using the experimental prototype, which enables the acquisition of cardio-electrophysiological signals from in vivo 3, 4 and 5 days-post-fertilization(dpf) zebrafish embryos.

In this second of a two-part review encompassing random, combinatorial methods for soluble protein 'domain hunting', we focus upon the expression screening from DNA fragment libraries. Given a library of domain length-encoding DNA fragments assembled in expression vectors, it is necessary to devise reliable means to screen the sample DNA fragment population to find those that express stable, soluble target protein fragments, suitable for the required downstream aims. This review summarizes a variety of alternative strategies that have been employed to identify such stable truncates of full-length proteins. In addition, we review measures that can determine the quality of the expressed protein, the likely reliability of these measures, and the apparent extent of their application within the featured studies.

Exploitation of potential new targets for drug and vaccine development has an absolute requirement for multimilligram quantities of soluble protein. While recombinant expression of full-length proteins is frequently problematic, high-yield soluble expression of functional subconstructs is an effective alternative, so long as appropriate termini can be identified. Bioinformatics localizes domains, but doesn't predict boundaries with sufficient accuracy, so that subconstructs are typically found by trial and error. Combinatorial Domain Hunting (CDH) is a technology for discovering soluble, highly expressed constructs of target proteins. CDH combines unbiased, finely sampled gene-fragment libraries, with a screening protocol that provides "holistic" readout of solubility and yield for thousands of protein fragments. CDH is free of the "passenger solubilization" and out-of-frame translational start artifacts of fusion-protein systems, and hits are ready for scale-up expression. As a proof of principle, we applied CDH to p85alpha, successfully identifying soluble and highly expressed constructs encapsulating all the known globular domains, and immediately suitable for downstream applications.

In addressing a new drug discovery target, the generation of tractable protein substrates for functional and structural analyses can represent a significant hurdle. Traditional approaches rely on protein expression trials of multiple variants in various systems, frequently with limited success. The increasing knowledge base derived from genomics and structural proteomics initiatives assists the bioinformatics-led design of these experiments. Nevertheless, for many eukaryotic polypeptides, particularly those with relatively few homologues, the generation of useful protein products can still be a major challenge. This review describes the basis of efforts to forge an alternative 'domain-hunting' paradigm, based upon combinatorial sampling of expression construct libraries derived by fragmentation of the encoding DNA template, namely the methods and considerations in generating fragment length DNA from target genes. An accompanying review focuses upon the expression screening of such combinatorial DNA libraries for the sampling of the corresponding set of protein fragments.

The mitochondrial (MT) genome is a potential means of gene delivery to human cells for therapeutic expression. As a first step towards this, we have synthesized a gene coding for mature human ornithine transcarbamylase (OTC) by recursive PCR using 18 oligodeoxyribonucleotides, each 70-80 nucleotides in length, using codons which should allow translation in accordance with both mammalian mt and universal codon usage. Flanking mt DNA sequences were incorporated which are designed to facilitate site-specific cloning into the mt genome. Expression of this human gene in Escherichia coli leads to an immunoreactive OTC product of the correct size and N-terminal amino-acid sequence, but which forms inclusion bodies and lacks enzymatic activity.

This article explores how the UK’s biotech firms have evolved in response to their financial environment. As investors’ expectations about the potential of biotech have changed, funding options have opened up and closed down, leading firms to develop new business models and routes of technology development. After a favorable period, new constraints on stock market funding have forced UK biotech firms to compress their life cycles, constraining their ability to generate the late-stage drug candidates sought by large pharmaceutical firms. These changes are analyzed within a neo-Chandlerian framework in the context of a selection environment where rather than firms of varying inefficiencies being selected by an efficient market, we find entrepreneurs submitting themselves to an inefficient investment-selection process at the intersection of industries attempting to achieve their own scale economies. The article highlights the importance of the scale of investment at the firm and industry level, and suggests that decline in the size of the industry can have adverse consequences for investment and firm performance in this setting.

This dissertation, by comparing the agricultural biotechnology sector in the
Netherlands and the UK, aims to understand the advantages and disadvantages
posed by intermediary organisations for the promotion of knowledge exchange
between universities and industry. An original conceptual framework has been
constructed to allow a systematic analysis of intermediaries according to the
functions they fulfil. The framework suggests that intermediaries can fulfil one or
more of the following functions: access to human resources, access to the
knowledge base, opportunities for commercialisation, access to facilities and other
infrastructure, and access to networks. In order to move beyond the limitations
brought about by differing nomenclature for intermediaries, the framework also
proposes four ideal types of intermediaries derived from an analysis of existing
intermediaries. The results of the empirical study reported here show that the
roles of intermediaries are dependent on the characteristics of the sector as well as
the history and configuration of existing national institutions. The policy
implications of this study are several-fold. It is shown in this dissertation that
application of certain dominant models of intermediaries can result in
disadvantages for sectors like agricultural biotechnology that differ in important
respects from the more frequently studied sectors, where these intermediaries
seem to work better. This study of the agricultural biotechnology sector showed
that there is space for new configurations of intermediaries such as sectoral
technology transfer companies. The study highlighted that the crucial element for
knowledge exchange is the production of knowledge itself. After identifying certain
weaknesses in the UK agricultural sector and strengths within the Netherlands, the
dissertation finds that large collaborative programs tend to facilitate knowledge
exchange, while collaborative research and training can be a path for overcoming
weaknesses in the system. By comparing the Netherlands and the UK, this study
also showed that the presence of a strong industry is necessary for the uptake of
knowledge originating from the research base.

The development of novel protein therapeutics relies on the ability to express appreciable amounts of correctly folded recombinant proteins. Latent IFN-β is engineered using the latency-associated peptide (LAP) of transforming growth factor β1 (TGF-β1) to maintain IFN-β in a biologically inactive form until such time as it is released at sites of inflammation by matrix metalloproteinase activity (see Adams et al., 2003). CHO cells cultured in suspension were used for expression of latent IFN-β to allow medium scale transient transfection. However, the recombinant protein expressed in this system consisted of a mixture of properly linked disulphide dimers and monomers. The ratio of dimer:monomer produced could be significantly altered towards increased dimer production by the addition of L-cystine to the CHO culture medium. The total yield of latent IFN-β was increased by co-transfection of plasmid coding for the simian virus (SV) 40 large T antigen to the plasmid with the SV40 origin of replication expressing latent IFN-β DNA. These results provide valuable new insights for developing protocols to produce substantial quantities of latent cytokine dimers in CHO cells in suspension.

fMRI experiments with awake non-human primates (NHP) have seen a surge of applications in recent years. However, the standard fMRI analysis tools designed for human experiments are not optimal for analysis of NHP fMRI data collected at high fields. There are several reasons for this, including the trial-based nature of NHP experiments, with inter-trial periods being of no interest, and segmentation artefacts and distortions that may result from field changes due to movement. We demonstrate an approach that allows us to address some of these issues consisting of the following steps: 1) Trial-based experimental design. 2) Careful control of subject movement. 3) Computer-assisted selection of trials devoid of artefacts and animal motion. 4) Nonrigid between-trial and rigid within-trial realignment of concatenated data from temporally separated trials and sessions. 5) Linear interpolation of inter-trial intervals and high-pass filtering of temporally continuous data 6) Removal of interpolated data and reconcatenation of datasets before statistical analysis with SPM. We have implemented a software toolbox, fMRI Sandbox (http://code.google.com/p/fmri-sandbox/), for semi-automated application of these processing steps that interfaces with SPM software. Here, we demonstrate that our methodology provides significant improvements for the analysis of awake monkey fMRI data acquired at high-field. The method may also be useful for clinical applications with subjects that are unwilling or unable to remain motionless for the whole duration of a functional scan.

At the core of any effort by a nation state to regulate new technologies for public release is an implicit navigation of uncertainty. The case of Bt cotton in India presents a very timely and pragmatic example of how nation states grapple with uncertainty in a regulatory context. While much attention has been given to how government actors form regulation, far less is given to how actors outside of the government spheres act as catalysts for regulatory reform. In practice, it is often these parties that drive regulation as a process. The question is how.

This paper outlines the findings of fieldwork conducted in India between March 2007 and July 2009 in addressing this central question: what does regulation really mean in a context where new technologies burdened with uncertain consequences are introduced? How do preferences, decisions, and regulatory norms adapt to this introduction based on the interactions of a multitude of parties acting on multiple framings of understanding what risk means?

The conclusion is that regulation – in the context of Bt cotton in India - is far from a set of government policies derived from scientific measures of risk assessment. Civil society, firms, and farmers themselves all have tremendous influence on how a nation state navigates uncertainty in a regulatory context. It is a process forged on risk interfaces, where constructions of risk both complement and oppose one another. The actors involved enter these spaces, invited or otherwise. What the government may have initially imagined as ‘regulation’ is subject to multiple technical, economic, and political framings of risk from each actor. As a result, regulation is a coevolutionary, co-constructed process. This process of negotiating these spaces is what regulation really means.

Vigorous debates have taken place in many European countries, and between the EU and
the USA, about regulatory policy regimes covering the assessment and approval of GM
crops. In such countries the debates have, to a large extent, taken place in public arenas
and with the active participation of broadcast and print media. In Iran, a very vigorous
and hotly-contested policy debate concerning legislation covering GM crops took place
between 2004 and 2009, but it was almost entirely confined within the Government with
no public debate and minimal media coverage. From early 2006 to late 2008 a protracted
dispute occurred between different parts of the Iranian regime, which was characterised by
an apparent stalemate. In 2008-2009, conspicuous policy shifts occurred, which
culminated in the passage of a Biosafety Law by the Iranian Parliament (or Majlis). This
thesis describes, analyses and explains the policy-making process from 2006 to 2009. It
explains firstly how and why a stalemate arose in the disputes between ministries and
departments. It then explains how that impasse was overcome, and how a particular policy
regime came to be adopted. The chosen analytical framework draws mainly on two bodies
of literature, namely the regulation of technological risk, and the analysis of public policymaking.
A task-specific analytical framework is developed which uses the concept of the
‘framing assumptions’, which underpin the particular positions taken by the diverse
protagonists in the debate, to analyse the characteristics of the seemingly irresolvable
dispute. The differences between those framing assumptions are used to provide an
explanation of why the stalemate arose and remained unresolved for several years. The
explanation of the eventual policy outcome takes account of those framing assumptions,
but on their own they are not sufficient to explain the eventual policy decisions. To
provide that explanation, considerations of the unequal division of political power
between parts of the Iranian regime are required. The Iranian case study, despite some of
its unique characteristics, can support several general conclusions about the dynamics of
risk policy making, the conditions under which disputes can arise and those under which
they may be resolved.

This study is a qualitative analysis to investigate the extent and characteristics of the influence of the national system of innovation (NSI) on the performance of the biotechnology sector in a developing country. While developing country ̳leapfrogging‘ would, at first sight, seem to contradict mainstream theorising about latecomer innovation, it fits well with a Gerschenkronian focus on therole of substitutes to overcome major stumbling blocks to economic developmentand the role of institutions such as banks in directing investment. This makes it compatible with an older, more traditional literature. Yet, even though such success can readily be understood for scale-intensive heavy industries with well-established technological trajectories, it does not seem so simple for biotech, where success is still highly uncertain, even for firms in developed countries, and where directed governance structures of the sort authors such as Gerschenkron highlight are not normally deemed useful. To identify what influences the uneven performance of the bioagricultural and biopharmaceutical sectors in Iran, a parallel approach to Gerschenkron‘s is implemented in this thesis, to determine whether the characteristics of Iran‘s NSI in biopharmaceuticals differ from those of bioagricultural sector and whether these differences explain the differing performance. The study makes extensive use of interviews as well as documentation to assess the actual unfolding of events. The findings were unexpected at the outset of the project as the uneven development in the biotechnology sector of Iran turns out to have been caused less by technological failure than by regulatory failures on the part of government. This demonstrates that while the government can speed up economic development by overcoming barriers (through for example promoting successful access to technological knowledge, research and development), it can also hamperinnovation by failing to provide appropriate legislation and to adjust laws and regulations to the stage of technological development that the biotechnology sector of a developing country has achieved. Thus Gerschenkron‘s conclusion about the state as a substitute for ̳economic backwardness‘ is turned on its head