2019 Student Cohort

AdStem cell-secreted exosomes are gaining significant attention as a candidate therapeutic platform for 21st century healthcare. This is because a growing body of research into exosomes has revealed that they can drive desirable behavioural changes in target cells, modifying or reversing pathological processes. The potential applications of exosomes are broad and include cell-free regenerative medicine at one end of the spectrum and cancer therapeutic at the other. To fully understand the therapeutic repertoire of exosomes, it is necessary to systematically characterise exosome populations isolated from a range of different cell culture scenarios. Critical for commercial development, it is also necessary to generate exosomes in therapeutically relevant quantities, which requires the creation of a cell culture process that can be scaled up to deliver industrial quantities of exosome product. Using bench-scale bioreactors that mimic industrial bioreactor technologies, this project will draw on expertise across bioprocess engineering for regenerative medicines in order to scale up production of stem cells and their exosomes. It will then use microfluidics and analytics for in vitro testing of exosome potency. This can be achieved using automated, perfused cell culture devices that support in situ monitoring of how exosomes influence the behaviour of 3D microtissues. 3D microtissues will be created using cells and biomaterials to create self-assembled tissues. The microfluidic devices will result in minimal operator error and increased measurement consistency.

Understanding MSC-EV trafficking, tropism and tumour targeting is urgently required to support clinical translation. The proposed project will focus on unravelling the mechanisms controlling MSC-EV migration to tumours and lymph node metastases. This will involve development of a clinically relevant microfluidic device to study trafficking of therapeutic extracellular vesicles to patient breast tumours and lymph node metastases.

Use of stem cells has the potential to transform regenerative medicine, if appropriate strategies can be identified for the controlled differentiation of these progenitors. One way to control stem cell differentiation in the lab is to use small signalling molecules like the synthetic steroid dexamethasone. This approach can’t generally be used in patients though, because the required drug concentrations are too high, and would lead to major side effects. We’re trying to overcome this limitation using several related methods, including developing more potent compounds, and exploring the possibility of delivering drugs directly at the site of action. We’ve got some preliminary results that look promising, and hope that you’ll join our team to help carry this work forward.

Current 3D diabetic foot ulcers (DFU) models are inadequate for preclinical testing of therapies or wound dressings and, therefore, further development is ongoing. The aims of my research proposal are based on identified lapses in the literature, whilst addressing all remits of the lifETIME CDT training:
– To develop a more biologically relevant 3D DFU model with a well-defined physiological matrix and
microenvironment, consisting of different cell types present in DFUs in vivo;
– To test the performance of the developed 3D DFU model with some therapeutic approaches;
– To render its fabrication scalable for scalable production using the Advanced Manufacturing Pilot Line at the National Centre for Laser Applications (NCLA), NUIG

Research Group – http://ncla.ie/

The PhD project is of an interdisciplinary nature and lies at the interface of bio-engineering, biophysics and medicine and will focus on developing and engineering new methods for improved, accurate detection and assessment of TBI as well as understanding, monitoring and controlling the cellular and tissue responses to therapeutical treatments. Overall aim will be focused towards development and implementation of advanced technology for in-vivo human eye-Safe mMultiplex resonance Raman (ESMR2) device for Point-of-Care neurodiagnostic. By diagnosing, monitoring and clinically evaluating treatments for TBI patients through better understanding of underlying mechanisms of the diseased tissue and organs (brain, eye), the outcomes of this research will lay a platform towards revolutionizing the ways we improve the health and quality of life for millions of people worldwide.

Research Group – https://anmsa.com/

Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults. AML is caused by the acquisition of mutations in haematopoeitic stem cells (HSCs), leading to the development of leukaemic stem cells (LSCs). LSCs within the protective bone marrow microenvironment may become quiescent, rendering them resistant to treatment by antineoplastic drugs. This can cause AML relapse, and despite recent advances in therapy, this will happen to around 50% of patients. Relapsed AML is a key area for further study as therapeutic options are limited and patient survival is very low. One major challenge in treating these patients is overcoming this protective environment provided by the bone marrow niche. The aim of this project is to explore the efficacy and selectivity of the CDK 2/9 inhibitor fadraciclib, alone and in combination with novel therapies, using a 3D humanized in vitro niche system. Potential combinations with fadraciclib include venetoclax, a BCL-2 inhibitor; azacytidine, a hypomethylating agent; and cytarabine, an antimetabolite.
The project will provide exposure to a broad array of cellular and molecular techniques including bioengineering and cutting-edge single cell PCR, RNAseq and ChIP-seq technologies. These experiments will identify the most potent combination therapies for relapsed AML that can be taken forward to clinical trials. Key to this project is understanding the role of the bone marrow niche in resistance to AML therapies, and in vitro co-culture 3D models will provide highly important data to better understand this critical issue.

The development of safe and effective therapies to treat fibrosis is a major priority for patients with glaucoma. This ocular disease is characterised by elevated intraocular eye pressure (IOP), resulting from ineffective drainage of the aqueous humour. This in part is caused by the blockage of the aqueous humour outflow due to increased extracellular matrix deposition in the trabecular meshwork (TM). Over time, the increased pressure can damage structures in the eye resulting in vision loss. The lack of safe and effective anti-fibrotic treatments presents an important clinical challenge and therefore, there is an urgent unmet need to identify novel targets for anti-scarring drug development.
Together with a team consisting of ocular biologists, biomaterial scientists, tissue engineers, and clinicians and, with both international (USA) and industrial placements (Cell Guidance Systems Ltd), this PhD project will develop, for the first time, state of the art in vitro and ex vivo human and porcine models to induce and treat scarring that occurs in the eye’s anterior segment in glaucoma. Once developed, these models will be used to screen new anti-scarring treatments suitable for further translation into the clinic.

Cancer metastasis or recurrence after therapy accounts for at least 90% of mortality from most cancer types and is an area of great unmet need for patients. Recent developments in our understanding have shifted the focus to cancer dormancy, a quiescent state whereby cancer cells can remain below the level of detection in the body and eventually reawaken. There are currently very few models for dormancy. Recent developments in biomaterials have provided tuneable and reproducible hydrogels to model the cancer microenvironment that we will exploit to develop models for drug screening and molecular interrogation. The successful student will develop in vitro 3D models to recapitulate cancer dormancy in cooperation between the Glasgow CRUK Beatson Institute and Centre for Cellular Microenvironment at the University of Glasgow and the company BiogelX. Lab skills include: hydrogel development, 3D printing, cancer spheroid growth and manipulation and advanced imaging methods she/he will undertake internship periods with BiogelX to develop a deep understanding of the translation of such assays from an academic lab to commercial products. This exciting multidisciplinary project will address a major unmet need in cancer recurrence and metastasis therapy.

Elena will use a range of microscopic techniques (including the Mega-FLIM system we are developing with Physics) to measure self-generated gradients in 3D cell aggregates, organoids, and embryoids, using fluorescent receptor and G-protein probes.

Vascular grafts have been for 50 years the established practice for the replacement of any diseased segments of aorta from the aortic valve to the iliac bifurcation. Two of the main clinical problems of these medical devices are the risk of infection and risk of thrombotic stenosis due to the material’s pro-thrombogenic activity which typically lead to new surgeries. It has been hypothesised that the lack of endothelisation of these grafts could significantly contribute to these problems. This project will develop new bioactive coatings that can be applied on existing grafts to maximize the process of endothelisation and develop next generation of vascular grafts. The project will be developed between the University of Glasgow and Terumo Aortic – a world leader in the fabrication of vascular grafts. This is a multidisciplinary project that will work at the interface between materials and cells. The project will implement state-of-the-art coating techniques to present bioactive molecules that promote the growth of endothelial cells on the wall of the vascular graft. The project will allow the student to develop skills in a number of experimental techniques including characterization of functional biomaterials, atomic force microscopy, confocal microscopy and cell and molecular biology at the interface between biomaterials and cells. It will also give them significant industrial exposure through close collaboration with and placements at the company.

Research Group – https://glasgow.thecemi.org/https://glasgow.thecemi.org/

This project aims to develop a multicellular in vitro 3D ‘organ on a chip’ system that incorporate immune cells, vasculature and primary human cells (including tumour and stromal cells). This will be used to study complex important interactions between the colorectal microenvironment and immune system to identify new immunotherapy targets for colorectal cancer.

Research Group – https://www.nuigalway.ie/medicine-nursing-and-health-sciences/staff-profiles/aideenryan/

The generation of cardiac organoids can be achieved by recapitulating, as close as possible, the native microenvironment of the myocardium. The purpose of this PhD project is to intertwine the fields of bioengineering, biochemistry and immunology, by combining macrophages; key cells of the innate immune system, with cardiac organoids to achieve a more physiologically relevant model and achieve a diseased ‘heart-attack on-a-dish’ organoid model as a patient specific pharmacological testing platform.

Research Group – https://www.monaghanlab.com

Maintenance of bone and cartilage is essential for healthy ageing. These tissues can be pathologically perturbed in diseases such as osteoarthritis or compromised in accidental injury leading to non-union fractures. Therapeutic options in these settings are limited and it is therefore paramount that studies are undertaken to develop new therapeutic strategies. Recent technological advances in human stem biology, genetic editing and 3-dimensional cell culture, means that it possible to undertake studies with primary human cells that can reproduce in vivo and pathological settings. Prior work in our laboratory has identified pathways that play major roles in new bone formation and cartilage maintenance. This raises the possibility that modulation of these pathways can be used to treat pathological aspects of osteoarthritis and/or enhance fracture healing in cases of non-union fractures. In order to achieve this, several steps need to be undertaken. This studentship will focus on (a) using reprogrammed human induced pluripotent stem cells to generate cells essential for bone and cartilage generation (e.g. osteoblasts and chondrocytes) (b) applying CRIPSr technology to genetically modify pathways so their therapeutic utility can be determined and (c) integrating controllable 3D gels to model tissue environments. Combined, these studies will provide unique insights into human bone biology and how cell-based therapeutics can be harnessed to treat/repair pathological and accidental damage.

Research Group – https://daveadamslab.com/ and https://glasgow.thecemi.org/