University of Galway Research Repository
Open access to publications, including peer-reviewed articles, conference papers, working papers, reports, and other scholarly communications by University of Galway researchers.
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Publication Mechanotherapies for Type 1 diabetes: Using actuatable medical implants to understand and modulate the foreign body response(University of Galway, 2024-10-04)Type 1 diabetes is a chronic, lifelong condition for which there is no cure. The disease is characterised by autoimmune destruction of pancreatic beta cells, rendering them unable to produce insulin. This leads to hyperglycaemia, which can have fatal consequences if untreated. Management of the condition currently necessitates stringent glycaemic control via blood glucose monitoring and insulin therapy which can be burdensome for the patient and result in sub-optimal glycaemic control. Continuous subcutaneous insulin infusion sets, or insulin pumps, have greatly improved therapeutic outcomes for type 1 diabetes patients in recent years. However these devices have a short lifespan and must be replaced approximately every three days, in large part due to device occlusion as a result of the foreign body response. The foreign body response is the body’s defence mechanism towards an implanted object and results in the deposition of a dense, hypopermable, fibrotic capsule around the implant. In the case of insulin infusion sets, the presence of a fibrotic capsule can impede the diffusion of insulin out of the device and intro the surrounding tissue. An alternative therapy for the treatment of type 1 diabetes is the transplantation of insulin producing cells – derived either from cadaveric donors or differentiated from allogenic stem cells – to replace the patient’s dysfunctional beta cell population. Whilst this approach has shown promise, current protocols require co-administration of a harsh immunosuppression regimen to prevent allogenic rejection of the transplanted cells. Immunosuppressive medications are associated with a wide range of side effects, the risks of which often exceed the disease associated risks meaning this is a non-viable treatment option for many patients. To eliminate the need for immunosuppressive medication, there is interest in transplanting insulin producing cells within an immune isolating barrier known as a macroencapsulation device. Macroencapsulation devices house transplanted cells within a semi-permeable membrane which permits the exchange of glucose, insulin, and essential nutrients required for cell survival and function, whilst preventing the infiltration of harmful immune cells. However, the presence of this membrane poses a diffusion barrier between the cells and the host environment, limiting molecular exchange and compromising cell viability. This is exacerbated by formation of a fibrotic capsule which further impedes diffusion of essential molecules, ultimately leading to cell hypoxia. A potential means to modulate the deposition of this fibrotic capsule is to mechanically actuate the implant, which perturbs the local tissue environment and thus interferes with the production of fibrotic tissue. The first study of this thesis (Chapter 3) investigated the effect of intermittent actuation of an implanted insulin delivery device on fibrotic capsule formation and drug delivery kinetics. The device was implanted subcutaneously in mice for up to eight weeks, with five minutes of actuation performed twice daily. This study found that after eight weeks of intermittent actuation, insulin transport was non-significantly different from baseline (three days post implantation) levels, in contrast with non-actuated control devices which had significantly reduced performance and had become functionally redundant at eight weeks. A number of cellular and biological factors could be attributed to this outcome, including that actuation of the device resulted in a significantly reduced the number of inflammatory cells at the implant site (reduction in neutrophils at day five, and reduction in myofibroblasts after two weeks), significantly reduced capsule thickness after two weeks, a significant increase in capsular collagen coherency after eight weeks, in addition to reducing tissue infiltrate present in the device after eight weeks. The combination of these factors facilitated improved insulin diffusion out of the device and into the surrounding tissue to facilitate glucose uptake. Leading from this work, the next study of this thesis (Chapter 4) further investigated the mechanism of action underlying actuation mediated modulation of fibrotic capsule formation using a custom in vitro model. In this study, a human myofibroblast cells (WPMY-1 cell line) were seeded onto actuatable reservoirs, which were actuated for five minutes every 12 hours. This study found that intermittent actuation significantly reduced collagen production by these cells (after nine and 14 days), significantly reduced pro-inflammatory cytokine production (transforming growth factor-β1 after four, nine, and 14 days and interleukin-1β after four and nine days), whilst also upregulating the production of the anti-inflammatory cytokine interleukin-10 after 14 days. Using analytical and computational models to predict the strain and fluid flow levels that elicited these anti-fibrotic responses, this chapter begins to establish design parameters for the design of actuatable implantable cell encapsulation devices that can modulate the foreign body response. These design parameters were then used to inform the design of a novel actuatable macroencapsulation device (Chapter 5). Previous iterations of our actuatable implants have never been used for cell encapsulation. This actuatable macroencapsulation device was conceptualised on the premise that intermittent actuation of implantable drug delivery device (described in Chapter 3) can improve the diffusion kinetics in the local implant environment, which may also promote exchange of essential nutrients required for encapsulated cells to survive and function. Chapter 5 describes the design, manufacture and mechanical characterisation of an actuatable macroencapsulation device, in addition to the evaluation of cell encapsulation materials to support the viability and function of encapsulated cells. A murine mesenchymal cell line previously transfected with either Firefly or Gaussia luciferase was used to evaluate the longitudinal viability and function of the cells respectively. The macroporous, gelatin based scaffold material ‘Spongostan™’ (Johnson & Johnson) was found to support optimal cell viability and function. Actuatable macroencapsulation devices containing cells encapsulated in a Spongostan™ scaffold were then actuated for 10 minutes every 24 hours for the study duration of 13 days at an actuation magnitude that has previously demonstrated immunomodulatory effects (Chapters 3 and 4). Longitudinal bioluminescent imaging indicated that actuation did not compromise the viability of the encapsulated cells. Finally, a preclinical model (C57BL/6 mice) was established to evaluate the performance of the new actuatable macroencapsulation device in vivo, and an initial pilot study was conducted to evaluate the survival of encapsulated cells and understand the local and systemic immune response to the device. Bioluminescent imaging was used to non-invasively monitor the viability of cells encapsulated within the device which was implanted subcutaneously. Longitudinal blood sampling and flow cytometry methods were used to assess immune cell populations in the blood, and ex vivo tissue analysis was performed to evaluate formation of the fibrotic capsule around the implant. Collectively, the research presented in this thesis investigates how intermittent actuation of medical implants can be used to modulate the host foreign body response, and uses a combination of in silico, in vitro, and in vivo methods to design, develop, and evaluate the first actuatable macroencapsulation device. Findings from this thesis will inform further development of the device, which may have the potential to overcome critical limitations of current macroencapsulation approaches.Publication The performance and politics of home: Artist-led transnational perspectives in the 21st century(University of Galway, 2024-10-03)This performance as research PhD examines the performance and politics of home from an artist-led transnational perspective with cases studies situated in Galway, Gaza and Mexico City. The research examines how embodied experiences of home are created and/or challenged through performance and performative action with a focus on the female body and agency, personally and politically. The thesis argues that performances of home and/or performative acts reconfigure spaces of home thus changing how these spaces may be encountered, considered or experienced. It also argues that performances of home may facilitate agency mobilizing political changes or shifts in political power on both local and global levels. The research context explores the transnational socio-political contexts of these sites that directly and significantly inscribe embodied experiences and the lived reality of home. It investigates the potential of performance and performative acts in reconfiguring spaces of home, particularly those that occur within public space and domains, encompassing an analysis of performance in public space as acts of resistance, reassurance and resilience. A performative analysis of home indicates that spaces of home must be considered along a continuum of habitat including public and digital spaces, demonstrating that public space is essential to ideas and experiences of home. Performance is thus both a methodology and a theoretical lens, and the research is founded on collaborative practice with artists from Galway and Mexico City, relationships with artists in Gaza formed over the past four years, and my practice as an independent theatre artist in Galway. Ethical frameworks based on relational experience, collaboration, respect and exchange guide this research. The central themes of home and performance encompass a wide range of topics including space, ownership, citizenship and belonging around which discourse has changed significantly due to the global pandemic of COVID-19; with the first Irish lockdown, occurring approximately 6 months after this dissertation began. The thesis investigates these changes in relation to how home may be performed through artistic practice and performative acts of home-making, exploring how meanings of home circulate culturally in each of the three sites in relation to landscape, memory and sense of place. This project argues that creating spaces of home performatively, corporeally, and materially is of particular significance to communities within contexts of precarity, injustice and violence. Fundamentally, this study proposes that by analysing home through performance, meaningful and substantial new insights are generated into how concepts of home may be constructed and experienced, which are of significant social, political and cultural value in an era when home is in crisis.Publication A novel tool based on reduced order grey box model to support the estimation of the energy savings in building retrofits(University of Galway, 2024-10-03)Buildings account for about 40% of energy consumption in the European Union (EU) and 36% of greenhouse gas emissions, making them the largest energy consumer in Europe. Energy performance contracting (EPC) as a tool to improve the energy efficiency of buildings can accelerate investments in cost-effective energy conservation measures (ECM) for existing buildings. However, there are many risks and barriers that can slow the adoption of EPC, such as the complexity of the process or the uncertainty of building performance after retrofit. The International Performance Measurement and Verification Protocol (IPMVP®), originally developed to encourage investment in energy and water efficiency, energy management, and renewable energy projects, has the potential to reduce some of the EPC barriers. However, due to limited and uncertain information about existing buildings, applying this measurement and verification protocol to retrofit projects is often complex and requires the use of novel building simulation tools. To address the challenges of applying IPMVP® in building retrofit projects, promote the adoption of EPC, and reduce greenhouse gas emissions in the EU, the research presented here developed ModSCO, a web application that supports a systematic assessment of energy performance using a novel Reduced Order Model (ROM) that can be used for (i) systematic quantification of energy savings achieved by ECMs (avoided energy consumption) and (ii) direct estimation of energy savings by exploring different building envelope retrofit scenarios. This thesis begins with a review of Energy Performance Contracting, followed by an research of the methodology based on ROM, which was chosen to overcome the EPC barriers. The thesis proceeds to describe the Reduced Order Grey Box Model (ROM), which serves as the core of ModSCO, the tool facilitating the estimation of energy savings in energy efficiency projects. A number of case studies are then discussed to demonstrate the accuracy and benefits of using the ROM as a novel method for estimating energy savings in building retrofits. Next, a description of the ModSCO web application and thus the front-end of ROM is presented along with a case study. Finally, the benefits derived from the research, the results and future work are discussed.Publication The potential of neurotrophin-loaded biomaterials to enhance stem cell-derived brain repair for Parkinson's disease(University of Galway, 2024-10-03)Extensive preclinical and clinical research have demonstrated the potential of cell-derived brain repair for Parkinson’s disease showing that cells can survive, integrate and reinnervate the Parkinsonian brain ultimately providing functional recovery to patients. Although the historical source of dopaminergic neurons for cell replacement therapies had been foetal-derived cells, the ethical concerns related to their supply and various logistical issues have encouraged the field of brain repair to switch towards the transplantation of stem cell-derived dopaminergic progenitors. A multitude of preclinical trials have shown that these cells can survive, differentiate in situ and provide amelioration of motor deficits in animal models leading to the initiation of four clinical trials with the aim to test safety, tolerability and efficacy of both embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC)-derived grafts for patients. However, the preclinical literature suggests poor in vivo survival and maturation of these progenitors undermining the realisation of the full potential of stem cell replacement therapies. In this context, injectable biomaterials have the potential to address these challenges. Specifically, neurotrophin (NTF)-loaded biomaterials could provide the transplanted cells with long-term NTF delivery overcoming the issue of trophic withdrawal post-grafting. Moreover, injectable in situ gelling collagen hydrogels could provide supportive benefits by acting as a matrix for cell adherence, by creating a physical barrier against the host’s neuroimmune cells and by providing the transplanted cells with a NTF-rich microenvironment to aid their survival after transplantation and consequent in situ dopaminergic differentiation. Thus, the overall aim of this project was to assess the potential of NTF-enriched biomaterials for enhancing in situ survival and maturation of human iPSC-derived dopaminergic progenitors in Parkinsonian rats, particularly in immunosuppressed (rather than immunodeficient) rats. Specifically, we firstly conducted a systematic review of the preclinical literature to assess the extent of survival and dopaminergic differentiation of human ESC and iPSC-derived dopaminergic progenitors (DAPs) in the brain of Parkinsonian models. We found that cell survival was very variable (between 0% and 500%) but relatively high, with a median of 51%. However, although also very variable (between 0% and 46%), dopaminergic maturation was poor with a median of 3% of the transplanted cells. Therefore, in an effort to improve survival and differentiation outcomes of cells in preclinical models, we firstly tested two systems - biomaterial microcarriers and engineered mesenchymal stem cells - for the delivery of glial cell line-derived neurotrophic factor (GDNF) in a sustained manner. However, these showed either to not being biocompatible or to not be suitable for co-transplantation with iPSC-DAPs. In parallel, a recently conducted study in our group showed the ability of a GDNF and brain-derived neurotrophic factor (BDNF) functionalised collagen hydrogel to dramatically enhance survival and differentiation of iPSC-DAPs in the brains of athymic nude rats (T-cell deficient) but not in the brains of cyclosporine suppressed rats (T-cell suppressed). Therefore, the focus of this research switched to the hydrogel. Particularly, we firstly studied the immunological profiles of athymic nude rats and cyclosporine suppressed rats after transplantation of iPSC-DAPs either alone, with NTFs, in a hydrogel or in a NTF-enriched hydrogel. We found that cyclosporine suppressed rats were not fully immunosuppressed at the time of transplantation as residual T-cell populations were found infiltrating the brains in the peri-transplant area and circulating in the bloodstream. Next, we used an alternative immunosuppression regime to assess the potential of a NTF-enriched collagen hydrogel for enhancing in situ survival and maturation of iPSC-derived dopaminergic progenitors in immunosuppressed Parkinsonian rats. Although the beneficial effect of this hydrogel was not as pronounced as seen in immunodeficient rats, in immunosuppressed hosts it still showed a beneficial effect on the corridor test performance, and in terms of consistency of survival and differentiation of the cells which generated significantly denser grafts compared to when transplanted alone. In conclusion, a NTF-enriched collagen hydrogel has the potential to improve the efficacy of stem cell replacement therapies in Parkinson’s disease by providing dopaminergic progenitors with a supportive microenvironment throughout delivery and during the first week post-transplantation. However, further studies are required to allow the NTF-enriched collagen hydrogel to realise its full potential in immunosuppressed hosts, rather than immunodeficient, and further functionalisation is required in order to achieve sustained neurotrophic factors delivery in the brain.Publication A BIM-based business process model to support systematic retrofit of buildings(University of Galway, 2024-10-03)The United Nations Intergovernmental Panel on Climate Change (IPCC) published a Special Report on the impacts of global warming of 1.5 °C above pre-industrial levels and related global greenhouse gas emission pathways, in context of strengthening the global response to the threat of climate change. The building and construction sectors are responsible for 39% of energy-related carbon dioxide (CO2) emissions globally and have a key role to play in reducing global warming. Most emissions occur during building operation, accounting for 28% of all energy-related CO2 emissions for space heating, cooling and lighting, whit the remaining 11% coming from materials and construction processes. Approximately two-thirds of the global building area that exists today will still exist in 2050 and over 40% of the European residential stock was built before the 1960s when building regulations on energy efficiency were very limited. Currently, building retrofits affect only 0.5-1.0% of the annual building stock, indicating a slow pace of change for the building sector. The European Commission seeks to double the rate of building retrofits by 2030, i.e. about 35 million buildings need to be renovated by 2030. Therefore, in order to meet the emission reduction target, of at least 55%, set by the European Commission, a significant increase in the rate and effectiveness of energy efficiency retrofits of existing building and the generation and procurement of renewable energy is required. Academic literature shows that several barriers prevent the retrofitting of existing buildings and the implementation of energy efficiency measures in buildings. The research presented here examines the potential to overcome these retrofit barriers by developing a novel guide that supports systematic procedures relating to building retrofit. The proposed workflow combines the benefits of Building Information Modelling (BIM) with the Business Process Modelling (BPM) technique. BIM is used for its capacity to create and manage information along the full life cycle of a building. BPM optimises the retrofit workflow by providing all relevant stakeholders with (i) the instruments that facilitate a better understanding of their roles and responsibilities in the retrofit process and (ii) the technological framework and data needed to efficiently implement BIM within a project. A BIM-based Renovation Plan was developed for retrofit existing buildings using the BPM, a graphical language that was adopted by the National BIM standards for the BIM implementation in industry and that was also ratified as ISO9510. The BIM Renovation Plan is then tested in four real world pilot projects, demonstrating its effectiveness across different retrofit contexts. The results show that the proposed workflow is versatile and adaptable to different project outcomes, improving the quality of retrofit interventions. Moreover, it enhanced the management of information throughout the entire building retrofit lifecycle. In fact, stakeholders have access to clear and up-to-date data, reducing errors and misunderstandings during project implementation.
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