2021 Student Cohort

Organ transplantation remains the only effective treatment for end-stage liver disease. However, current methodologies are limited by organ availability, failure of donor engraftment, and vulnerability of tissue to cryopreservation damage. Cell-based therapies provide a viable alternative approach to overcome traditional transplant drawbacks, such as the limited number of donors and transplant rejections. In this project, we will explore cell engineering techniques to introduce bio-orthogonal functionalities onto the surface of bone marrow-derived macrophages (BMMs). Bio-orthogonal chemistry will then be used to selectively decorate the cell membrane with polymeric materials that promote cell adhesion and interactions with the extracellular matrix to allow for better engraftment of BMMs to the surrounding tissue. This ambitious project is highly interdisciplinary in nature, spanning the boundaries of bioengineering, polymer chemistry, and medicine to improve our understanding of cell-material interactions and control cell behaviour, with potential for real impact. The successful candidate will receive training in a wide range of techniques in a unique academic and industrial environment in partnership with InSphero.

Neurodegeneration is defined as the progressive deterioration of one or more subtypes of cells in the central nervous system. Within the spectrum of neurodegenerative disorders, multiple sclerosis (MS) is one of the leading causes of non-traumatic disability worldwide. Clinical management and treatment of MS, specifically for those affected by progressive MS, is hindered by less-than-optimal diagnostic methods, which, as of today, are limited to MRI imaging and disability evaluation. Thus, there is a clear and immediate need to identify novel biomarkers of MS. This project will examine the utility of RNA species, metabolites, proteins, and exosomes as possible surrogate markers of MS pathology. With this in mind, and exploiting the latest advances in paper-based, lateral flow assays, microfluidics, and microelectronics, we will attempt to develop novel multi-plexed paper- and/or microfluidic-based platforms for analysing samples. When combined with functional neurological readouts, this next-generation POC device will benefit all MS community stakeholders, leading to an improved quality of life for people with MS.

The eye is a vital organ for our sense of vision, but there are currently no established in-vitro models for the anterior eye (including the transparent window to the eye [the cornea], and the crystalline lens which allows us to focus at different distances when we are young). This project will optimise a mechanical holder to mount porcine eyes (a waste project of meat production), a fluid pump mechanism to circulate biological fluids which can maintain the physiology of these tissues for 7-10 days, and the mechatronics to simulate blinking and the muscle contraction that controls eye focus. The PhD student will work as part of a multidisciplinary team including mechanical and electrical engineers, clinicians and surgeons to investigate the biological effects of contact lens and surgical implantation of intraocular lenses following cataract surgery and how optimal vision can be restored. Additional projects will include accelerating the ageing of the crystalline lens, such as through growth hormones and microwaves, to simulate fibrotic changes with time.

Type 2 diabetes (T2D) is a growing worldwide health problem that is caused primarily by a loss in ability to respond properly to insulin. Although there are drugs available for T2D, most do not address this insulin resistance. Therefore, there is a clear need for new drugs that directly treat this underlying pathophysiology of T2D. In recent years it has become apparent that insulin resistance in T2D is associated with a chronic low-grade inflammation of metabolic tissues, including adipose. The important role of inflammation in the development of insulin resistance in T2D highlights a key challenge to finding new insulin sensitising drugs: the need for drug screening platforms able to reproduce the complex cellular environment of chronically inflamed metabolic tissue. This PhD project will address this need by bioengineering 3D cultured human adipose organoids that reproduce the environments of both healthy and T2D adipose. To facilitate their use in drug screening, these organoids will also incorporate novel genetically encoded biosensors, allowing for real time assessment of cellular function in both the metabolic and immune cells. Once established, the adipose organoids will be used to identify and characterise novel insulin sensitising therapeutics for T2D.

World population is predicted to reach 10 billion by 2050. There is an increased need to find sustainable food alternatives to support this rapidly growing population. Livestock meat is not sustainable and moreover comes with a detrimental effect on the environment, as well as risks of food-borne diseases and antibiotic resistant bugs.
Cultivated meat is an alternative food technology that has the potential to offer a healthier and safer option for consumers without any of the drawbacks associated with livestock meat. It is genuine animal meat that doesn’t require animal slaughter and can be produced efficiently in a bioreactor by only using a small tissue sample from the animal. This is a relatively new concept that still requires significant research to reach affordability and the production scale to satisfy market demand.
Similar to livestock meat, cultivated meat will have a complex structure comprising muscle, fat and connective cells which will give it the taste and the nutritional value of meat.
This project will develop a bioprocess for cultivated meat production by using an approach that involves cell encapsulation in food-grade hydrogels and co-culture to reproduce the complexity of livestock meat.

Organoids are complex 3D self-organised cellular entities currently serving as exciting non-animal models. Although their role is to mimic tissue or organ function, they are still at an early development stage. Despite recent progress, organoids are still facing technical challenges in terms of their size and shape control, lack of immune cells, limited control of heterogeneity and cell identity within the organoid composition, limited mature function and lifespan, or even a lack of a concise regulatory framework surrounding the ethical concerns that might arise from their production and deployment. Besides the mentioned challenges, the lack of vasculature within an organoid will provide an impaired biochemical exchange, poor diffusion of nutrients and oxygen within the organoid’s composition that might lead to necrotic cores and a direct impact of its function and lifespan. Therefore, this project aims to engineer multifunctional artificial organelles or cell mimics to promote and sustain the vasculature in 3D disease model organoids using 3D bioprinted construct supports and microfluidic 3D cell culture devices. Ultimately, the organoid’s lifespan will be increased to achieve its designed function, thus unravelling novel mechanistic insights into various disease models.

Multiple Sclerosis (MS) is an auto-immune disease of the central nervous system. Its pathogenesis is complex initially resulting in intermittent, and subsequently, often progressive neurological defects. Several disease modifying therapeutics are available for the intermittent sub-type of the disease called relapsing-remitting MS, however very few interventions are available for the progressive form of the disease. Furthermore, development of therapeutics has declined, and the cost of development has risen. Models are an experimental system which aim to mimic aspects of physiology and pathology. Models can provide us with an insight into how diseases may develop and progress. Microscale models using microfluidics offer an interesting solution to the rising costs of research by reducing the reagents required they can reduce the cost and facilitate high throughput analysis. Microfluidics utilise a variety of physics concepts to create a predictable microenvironment, combining this physical environment with cell biology we get to the field of Organ-on-a-chip models. Which are exactly what they sound like, they aim to recreate organ functionality and structure on devices the size of a microchip.
The aim of this project is to develop a MS-on-a-chip device, which will mimic the pathology of MS by dividing the disease into components. Namely neural, immune, barrier and gut components, with the eventual goal of using this system to assess the efficacy of novel therapeutics. We will develop these components individually before integrating and optimising the system. This MS-on-a-chip system will require the use of a variety of materials available in CÚRAM and tools available in the National Centre for Laser Applications located in the National University of Ireland, Galway. The developed system will subsequently be validated by assessing the effect of established MS therapeutics in a series of blinded tests.

Tissue engineering is used to generate lab-based replacements for tissues which have been damaged or need replacement due to disease, following an accident, surgical excision or loss of function. The strategy is to develop 3D structures which mimic the natural tissue in terms of the biological and mechanical properties, this then allows for cell growth, development and differentiation into functional tissue. In this regard, hydrogels have an established track record as 3D models.
Bone tissue engineering is high profile due to the increased need for tissue replacement in trauma, tumour excision, disease (e.g. osteoporosis) or skeletal abnormalities. Engineered 3D materials for bone can make use of different stimuli, to accelerate the repair and regeneration of the tissue. In particular, magnetic stimulation can promote increased bone formation, allowing for a more rapid and better healing process. Static magnetic fields were found to accelerate cell proliferation, migration and the differentiation of osteoblast-like cells, as well as induce osteogenesis in bone marrow-derived mesenchymal stem cells (MSCs).
In this project, we aim to generate magnetic hydrogels for bone tissue engineering, which in combination with a static magnetic field, will act to accelerate osteogenesis in bone marrow MSCs.

Cancer therapy using immune checkpoint blockers (ICBs) whichregulate immune cells to target tumour have revolutionised cancer treatments. However, the success rate of ICBs in primary liver cancer remains low (~20%). The exact cause for the low response in liver cancer treatment using ICBs remains unclear. The liver is highly tolerogenic
which provides an unique environment to allow the immune system to get accustomed to foreign antigens. Liver sinusoidal endothelial cells (LSEC), which lines the fine blood vessels in the liver make plays an important role in contributing to the tolerogenic function by altering immune cell functions. We hypothesise that liver cancer programmes LSEC’s ability to regulate immune cells that enter the liver, making ICBs therapy less efficient in treating liver cancer. In this project, we aim to develop a novel three-dimensional patient-derived liver model to investigate the interaction between the tumour cells, LSEC and immune cells during liver cancer. We will identify what causes the changes in the LSEC and whether this can be prevented and eventually increase the efficacy of using ICBs in treating liver cancer patients.

Identifying and isolating rare target cells from a population is essential for diagnostics and fundamental research. Although fluorescence-based sorting techniques are commonly used, there are a vast diversity of applications, where fluorescence labelling is either not applicable or not desirable (e.g. when sorting cells for therapeutics).

This project will develop a versatile microfluidic system that integrates with Raman spectroscopy for sorting living cells based on their intrinsic biomolecular and optical image profiles. It will build upon on our pioneering Raman-activated cell sorting (RACS) microfluidic platforms, with new developments in machine learning and opto-microfluidics. The technology will use single cell Raman spectra that are characteristic of the phenotype, metabolic activity and function of a cell.

The outcome of this work will open a new avenue for ‘deep mining’ of untapped biological systems and facilitate the study of cellular metabolisms that are manifested in disease states. Within the project, depending on the student’s interests, the focus could be on the study of cancer cells at different stages to discover potential metabolic biomarkers for early cancer diagnosis and screening for potential treatments.

The project is highly interdisciplinary involving collaborations between engineers, cell biologists, and physical scientists. The student will gain a broad range of skills ranging from microfluidics, to imaging methods and analytical techniques, all in the context of studying the cell biology associated with different diseases.

Cornea is a transparent and protective layer in front part of the eye. Infections, persistent inflammation, trauma, and systemic disorders such as diabetes can damage the cornea tissue and leave millions of people blind. The blindness worldwide spread is approximately 39 million people. Of these, an estimated 15 million are visually impaired due to corneal damages. Effective cornea wound healing is a critical unmet medical need. Besides, the cornea is a highly innervated tissue and persistent inflammations can cause the nerves degeneration which are crucial for our vision. There are various treatments for ocular injuries such as surgeries, lasers, corticosteroids, and antibiotics, which all have a variety of side effects. Cell therapy is a new and innovative treatment that showed a high therapeutic efficiency in recent studies.

Mesenchymal stromal cells (MSC) can modulate inflammation and facilitate ocular repair and promote cell and nerve regeneration. Extracellular vesicles (EVs) that secreted from MSC (MSC-EVs) mediate some of the MSC therapeutic effects such as immunomodulation and regeneration. However, maintaining their biological activity and sustained and on-target release are the main obstacles in MSC-EVs therapies.

Biomaterials are promising strategies to address the EVs therapy limitations by entrapping the MSC-EVs and release them at the site of action in a controlled manner.

In this study, we aim to develop a biocompatible biomaterial which can encapsulate and deliver the MSC-EVs to the site of action with a controlled release profile. Also, we aim to study the therapeutic and regenerative potentials of the MSC-EVs-functionalized biomaterial in in-vitro 2D and 3D corneal cell and nerve models.

Being able to control haematopoietic stem cell (HSC) growth out of the body, out of their niche, is a major goal of stem cell biology. It would make HSC therapies, such as bone marrow transplant for leukemia treatment, more available by transforming them to become one donor – multiple recipient therapies. It will also allow us to develop in vitro niches to e.g. perform CRISPR on cancerous HSCs to provide autologous curative therapies.
In our laboratories, we have worked to understand how the partner cells of HSCs in their niche, the mesenchymal stem cells (MSCs), are regulated by materials interfaces. This is important as MSCs, that interact with the extracellular matrix in the niche, control HSC growth and self-renewal through cell-cell interactions and paracrine signalling. The understanding we have developed has enabled us to demonstrate that we can bioengineer in vitro niches where MSCs regulate HSC growth to maintain more of the most regenerative HSCs in culture for longer.
In this exciting new project, the student will develop 3D niche models for HSC growth using microbeads coated in our novel polymers that control how the extracellular matrix is presented to MSCs in order to produce HSC supportive MSC phenotypes. Further, we will work with our industrial partner, Atelerix, to place these marrow microtissues into their hydrogel systems that allow prolonged cell survival at room temperature. This step will be important for translation of our technologies into Pharma use by making them off-the-shelf, reproducible and easy to use.
The student will join a thriving lab with good links to clinic and to industry and where they will be provided with world-class multidisciplinary training. This will equip the student well for their next career steps.

Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90% of all pancreatic malignancies and has a 5-year survival and average survival of only 10–20% and 6–12 months after diagnosis, respectively. It is urgent to develop in vitro models that can contribute to dissect how the cancer microenvironment influences PDAC cells migration and infiltration to other organs. This project will combine engineered 3D hydrogels with controlled mechanical properties that inserted in microfluidic devices will allow generation of biochemical gradients and on chip investigation of cell migration in dependence of the mechanical and biochemical properties of the environment. The project is a collaboration between the Center for the Cellular Microenvironment and the Beatson Institute for Cancer Research. The project will develop bioengineering tools to answer cancer biology questions and will combine a range of techniques from biomaterials engineering to advanced microscopy.

The blood brain barrier is the protective shield on the central nervous system. As it controls the passage of molecules into and out of the brain it plays a key role in many biological functions and dysfunction in it is implicated in several diseases. Due to its complexity, investigation of the blood-brain barrier in vivo is challenging so there is significant interest in the development of synthetic blood brain barrier models.

In this project the structure and function of synthetic models of the blood-brain barrier will be investigated using a computational and experimental techniques. This will range from characterisation of protein adsorption onto the underlying polymer substrates to investigating the growth of endothelial cells that form the barrier. Investigating these BBB models across this wide range of length scales will give information needed to optimise their construction and use in investigate the BBB function and dysfunction.

Work packages
Protein adsorption onto polymer surfaces
– Atomistic MD
– QCM-D measurements

Formation of protein layer on polymer surfaces
– CG MD (using models derived from atomistic MD)
– AFM

Cell growth on protein layer
– Monte Carlo modelling
– Cell growth assays