2023 Student Cohort

All tissue engineering requires clinical trials prior to licensing and this PhD will develop the tools required to support efficient and detailed clinical ophthalmic metric collection at baseline and at timepoints after treatment. As well as being embedded in the doctoral training centre education and networking, the student will work closely with a start-up medical device company to experience all the stages of medical app development and certification within ISO 13485 to develop a patient management dashboard and modules to conduct visual function tests, utilizing the mobile / smartphones inbuilt camera and sensors. Data analytics will be applied to allow machine learning to aid future clinician decision making for personalized medicine. In addition, the student will develop and clinically validate apps for home monitoring of patients to aid and assess compliance and to give real-work symptomology data.

Cell based therapies using Mesenchymal Stromal Cells (MSCs) are an exciting therapeutic option, using our own cells to both dampen inflammation and promote repair of damaged tissues. Unfortunately, we require large numbers of these rare tissue progenitors for effective therapy, requiring expansion in the laboratory. This can result in loss of their important immuno-modulatory and repair functions due to spontaneous differentiation. We have developed a bioreactor methodology, where cells are expanded on microcarriers to provide a greater surface area for these cells to grow on whilst receiving defined growth conditions required for expansion of large numbers of functional cells.

In this project, you will build on this current knowledge to manufacture new microcarriers which can be optimized to provide both adhesive signals, and ‘tuneable’ elasticity to provide MSCs with the optimal growth surface conditions. This ‘tuneable’ new microcarrier system will incorporate slow release crystals allowing direct delivery of growth factors than can modulate MSC function. Importantly, these carriers will be degradable, allowing easy collection of expanded cells for further testing. This project will provide you with experience of bioengineering, as well as diagnostic assays used to phenotype and functionally analyse expanded MSCs to test their quality and ability to control immune cells. We will also investigate the soluble factors released by these cells in the reactor, such as extracellular vesicles, as these are known to be involved in immunomodulation. This multidisciplinary project will generate a new, customizable microcarrier platform to allow the efficient, standardised expansion of MSCs for use in therapy or scientific research.

Cardiovascular diseases (CVDs) are one of the current leading causes of death worldwide, constituting almost ⅓ of all deaths in 2019. CVDs progress due to many factors, such as the interaction between the immune system and vasculature. Studies have shown the potentially reparative effect of the immune system in healing after cardiac events and what occurs when these systems are dysfunctional. However, little is known about the mechanisms and interactions between the immune system and cardiac cells. We will utilise novel tissue engineering techniques to develop an accurate and tuneable in vitro model system for endothelial cells and accurately recapitulate macrophage-endothelial cell interactions following CVD events. We aim first to optimise a HyA hydrogel system, delivery of supportive extracellular
matrix (ECM) components and growth factors (GF) for vascular endothelial cell growth and development of vascular networks. Following this, we aim to introduce macrophages, polarised as anti- or pro-inflammatory as a co-culture with the endothelial cells to observe the interactions between the two cell types and the impact on vascular endothelial cell growth. Lastly, we aim to investigate this system and its interactions during and following CVD events by simulating a hypoxic/ischaemic environment.

As a PhD student, you will work with our partner Zimmer and Peacock Ltd, to develop novel advanced wearable biosensors, which can be used either for healthcare applications or assessing lifestyle and wellbeing markers. The devices, which will either be a watch or a patch/bandage will comprise microfabricated electrochemical biosensors to measure the metabolic activity of the body, non-invasively. The project will be built upon recent innovations to sample both interstitial fluid (ISF) and/or sweat from the skin, using a network of microchannels to carry the fluid to the biosensors. Such advances will dramatically expand the range and number of biomarkers that can be measured simultaneously.
You will obtain experience and knowledge in the development of wearable sensors including those to measure hydration state/electrolytes (important for the elderly and as an endurance exercise tool), pH (characteristic of metabolic disease) as well as more complex analytes including cortisol and adrenaline (for determining stress). Local near-field communications will send and data from the device to a smartphone, where signals will be interpreted using artificial intelligence,run on the GPU to deliver accurate and precise results to the end user.
You will also work with the wider public and other stakeholders (including clinicians) to understand the device design and how the wearable can best be used for healthcare and/or health and wellbeing.
Our partnership with Zimmer and Peacock will provide you with exposure to industrial applications within a vibrant research environment. The new methodologies will be demonstrated through a range of applications, tested in humans.

We are seeking a highly motivated student to undertake a multidisciplinary project to establish a plug-and-play microfluidic platform for sorting cells based on single cell Raman spectra (SCRS). SCRS contains rich information on the biomolecular composition of a cell, which reflects its type and metabolic function. Coupling SCRS with artificial intelligence and advanced optical imaging provides a powerful tool for discovering cellular traits associated with diseases (e.g. cancer). This project will work with oncology scientists and a global Raman spectrometer company (HORIBA) to discover and sort resistant cells against cancer therapies for downstream studies. This will facilitate the discovery of potential metabolic biomarkers for early cancer diagnosis and screening for potential therapies. The project is highly interdisciplinary, involving collaborations between engineers, cell biologists, data scientists and industry. The student will gain a broad range of skills ranging from microfluidics to imaging methods and analytical techniques.

Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancers worldwide and is often considered the most aggressive form of breast cancer, tallying 25% of deaths. The disease profile and tumour microenvironment (TME) of TNBC is poorly understood, and limited treatments are available. To develop efficacious and specific TNBC treatments, 3D in vitro models are necessary to understand better and emulate its microenvironment and to test and develop targeted therapies.
This project aims to build a 3D spheroid model of TNBC in vitro. This can be achieved by suspending TNBC cells and human vasculature-forming epithelial cells in a hydrogel matrix. We are especially interested in formulating hydrogels to emulate the native TNBC extracellular matrix (ECM). Commercial ECM options are available; however, these synthetic and natural designs have drawbacks, like imaging capabilities or accuracy, when used in vitro. By fabricating a novel hydrogel framework with components such as hyaluronic acid, we hope to provide more accurate replications of the tumour microenvironment. Targeted therapies we wish to test on this model include sandwich-like inorganic compounds known as metallacarboranes. These boron-metal clusters have shown TNBC cell death in vivo. So, their research can be furthered in the in vitro setting to identify new boron cluster conjugates to specifically target TNBC cells and elucidate the mechanism of action of known therapeutic metallacarboranes.
Overall, this project aims to produce an accurate in vitro model of TNBC, providing a testing platform for metallacarborane therapeutics.

Harnessing glycosylation in biomaterials presents tremendous opportunities for developing the next generation of regenerative strategies. Glycosylation of tissue substrates has yet to be studied comprehensively and systematically, as it is an exceedingly complex and variable modification. Elucidating the role of glycosylation in biomaterial development and applications requires an integrated approach marrying the knowledge and expertise of biomaterials, glycochemistry, and glycobiology. A systematic approach to developing and optimising glycosylated biomaterials in suitable biological systems is necessary to define the impact of glycans. In-vitro, functional evaluation of lectin-associated signalling in disease pathogenesis requires an established model for translating glycosylated biomaterials.
This project proposes the addition of glycosylated motifs to starting materials to tune these systems’ mechanical and biological properties to exert a regenerative effect. Using glycosylation in a multi-model fashion, with the tunability of physical properties,
degradability, tissue-material interactions, and downstream signalling, will be a ground-breaking approach in the field. The developed materials will be the characterisation of cell-specific differentially expressed glycans and lectins in relevant in-vitro models using lectin histochemistry, ELISA, immunohistochemistry, and PCR array for activation of lectin-related pathways. By developing suitable in-vitro models, we will study the role of glycosylated biomaterials in activating/inhibiting specific pathways in mixed-cell culture systems.
This project will validate appropriate models to test glycosylated biomaterials and determine the functional roles of lectins in disease. This will identify new disease targets amenable to modulation through other means should biomaterials fail. This ground-breaking approach to glycan functionalisation will open new opportunities for biomaterials in multiple therapeutic areas, adopting the principles developed.

The tumour stroma is a complex microenvironment in which components are recruited or remodelled to facilitate invasive tumour growth and spread of tumour cells to distant tissues. Therefore, specific focus is placed on understanding how the surrounding extracellular matrix (ECM), mainly collagen and fibronectin, is altered to mediate tumour progression. Hydrogels are water-swollen cell-friendly biomaterials, whose mechanical, structural, and biochemical properties can be tuned to mimic native ECMs, for application in tissue engineering or as in vitro models. However, standard hydrogels used in cell culture focus on their elastic mechanical properties and neglect to consider their viscous, dynamic nature. Hence, researchers are developing viscoelastic hydrogels with controlled viscous properties to control cell mechanosensing, lineage commitment of stem cells, or proliferation / invasion of cancer cells.
In this project, the student will fabricate and characterise viscoelastic hydrogels with varied viscoelastic properties with the aim of (i) mimicking the viscoelastic properties of the breast tumour microenvironment and (ii) understanding how cancer cells (3 types of cancer cells will be investigated, from non-aggressive to highly aggressive types) and control cells sense microenvironmental changes and respond to these properties. These studies will be performed both in 2D and more physiological 3D environments.
The project is expected to provide novel insights into how the in vitro microenvironment can be engineered to alter cell fate and stop tumour progression, invasion, and metastasis.

The field of skin research often relies on mechanobiology to understand the scar formation – inflammatory processes, through cell forces. However, the mechanobiology of gliosis and its relationship to scar formation after brain traumas are poorly understood. This project aims to understand the role of mechanobiology in gliosis after TBI and to exploit this knowledge to design new materials tailored to mitigate gliosis. The project will specifically focus on the part of the extracellular matrix (ECM) and glycans that produce critical interactions between the ECM and cell surface receptors modulating immunological responses. The mechanical forces produced at these biomolecular interfaces will yield information on cell wall tension that guides cytoskeleton development and phenotypic changes in cell function, typically seen in gliosis reactions.

Therapeutic biomaterial-based systems can revolutionise treatments for a broad spectrum of human diseases. Current research primarily focuses on using biomaterials as systems for targeted drug delivery with prolonged release profiles. Ultimately, these solutions exert a transient and limited therapeutic effect. Thus, there is a need to refocus biomaterial development towards inherent material bioactivity for sustained therapeutic effects rather than relying on exogenous therapeutic agents. Natural polymers are increasingly used in biomaterials for their bioactivity and biodegradability. These natural polymers can be surface engineered to display functional moieties to augment material properties. However, natural substrates are already modified with post-translational modifications (PTMs), which modulate material properties. Glycosylation, a PTM involving enzymatic conjugation of glycans to specific sites on proteins (N- and O-linked glycans), can augment properties such as cross-linking efficiency, material degradation, biomaterial delivery and immunoreactivity while providing sustained biological cues in biomaterials. This creates an opportunity to increase biomaterial bioactivity, precisely the material-host response. My research has focussed on elucidating the role of glycans in disease pathogenesis and demonstrating the change in the glycosylation in multiple myeloma, intervertebral disc degeneration and Parkinson’s diseases, amongst others. The present proposal proposes that glycosylated biomaterials can be delivered to a disease site to restore physiological glycan signalling in the tissue microenvironment with a beneficial functional effect—these glycosylated.

Cell immunotherapy has become a promising new cancer treatment; however, governing factors of successful tumour penetration still require optimisation. Recently, a subpopulation of T cells has shown the ability to induce a pro- and anti-tumour response depending on the cellular subset. These subsets have the potential to kill cancerous cells and support immunotherapy drugs once the biophysical processes governing tumour growth and immune infiltration are uncovered. Addressing this deficiency in scientific understanding will drive a paradigm shift in patient-specific cancer treatment. This project aims to develop 3D models to analyse T cell migration and infiltration to interrogate and uncover the biophysical processes underpinning biomechanical resistance to cellular penetration, ultimately guiding personalised healthcare frameworks for optimising anti-cancer immunotherapy. Experimental models of 3D breast cancer growth will be developed to gain a new understanding of the mechanical arrest of tumour cell proliferation. The models will determine the role of growth-induced stress, cell compaction, and matrix remodelling in restricting T cell penetration and whether this can be mitigated by pharmacologically perturbing tumour and immune cell mechanics.

The demand for animal-based foods will increase by 70% in 2050 to meet the 22.5% growth in global population. Yet, 800 million people worldwide already suffer from hunger and malnutrition, and the livestock industry contributes 12-18% of the world’s annual greenhouse gas emissions. Cultivated’ meat is an alternative way to produce meat which is safer and kinder to the animals and the planet compared to traditional methods. Replicating meat in vitro, however, is very challenging because of the complex nature of the final product. Furthermore, cultivated meat needs to match the organoleptic properties of conventionally produced meat in order to gain consumer acceptance. Additive manufacturing using 3D printing has already been explored in tissue engineering for the creation of artificial tissues and organs and therefore holds promise for the fabrication of scaffolds to support the formation of structured cultivated meat products. There are two different approaches to 3D printing in this context: (a) building porous acellular 3D structures which are seeded with cells post-printing; and (b) direct bioprinting of cell-laden biomaterials. Although 3D bioprinting can achieve accurate cell distribution, designing a suitable bioink is not an easy task. This project aims to combine edible polymers and 3D printing to create a scaffold material which possess structural and mechanical properties that support and maintain cellular viability and function, with the production of whole cut cultivated meat as the ultimate goal.

Rheumatoid Arthritis is a chronic inflammatory condition affecting 1% of the global population, but we still lack methods to predict disease phenotype or responses to drugs. Recent results obtained in our lab identify cell glycosylation as a potential target to overcome this scientific impasse.
All living cells are covered by a distinct layer of glycans [or sugars]. We know that a tight connection exists between the dysregulation of glycan expression and the onset of chronic inflammation, but the details of this process are still unclear, mostly due to the lack of suitable analytical methods. We plan to explore the adoption of Raman spectroscopy as an innovative label-free approach to explore the glycocalyx. This tool will shine a new light on the field of glycomics, enabling new scientific discoveries not only to provide more effective ways to investigate pathophysiological changes in cell glycosylation, but also to understand new aspects of cell biology to bridge inflammatory responses, structural glycobiology and mechanical properties of cells both in health and disease.
Moreover, thanks to the collaboration with an industrial leader in Raman instrumentation, HORIBA, we will address the potential of the approach to translate towards the clinic, designing a Raman-powered diagnostic device for inflammatory states.

Mesenchymal stem cells (MSCs) from the adult bone marrow can differentiate into cells that support the regeneration of tissues such as bone cartilage, ligament and tendon. They also have immunomodulatory properties and so are becoming more widely used as ‘drugs’ in transplant procedures to help prevent rejection e.g. in islet transplants and in graft vs host disease. Further, they can support the growth of the blood-forming stem cells of the bone marrow and can have regenerative roles in helping in blood diseases such as leukaemias. Therefore, they have the potential to provide a key role in strategies to underpin a wide range of next-generation disease therapies.
MSCs are isolated from the bone marrow in low numbers (1000s) and yet a cell therapy would require tens of millions of MSCs per dose and forming a company to supply the therapies would require the ability to produce billions of cells in order to meet the demand of healthcare suppliers at a cost that can be justified.
As MSCs grow in culture, out of the regulation of the bone marrow, they change phenotype (differentiate) and age (leading to the stopping of growth – senescence). To provide MSC therapies, both of these hurdles need to be overcome.
We have developed polymers that can control the presentation of extracellular matrix (ECM) proteins that MSCs interact with in the bone marrow in ways that allow for better MSC growth. ECM proteins contain cryptic peptide sequences that, when exposed, allow cell adhesion to them and allow signalling proteins, such as growth factors, to bind to them allowing better control of cell signalling.
In this project, we will study primary human MSC growth in relation to the biological presentation of the ECM proteins with growth factors in order to optimise MSC growth in vitro. We will use both biological (PCR, flow cytometry, qPCR, microscopy) and biomechanical (mechanical cytometry, nanoindentation and Brillouin microscopy) to look for markers of preserved MSC phenotype and senescence (eg stiffening of the cell nucleus). We will also employ transcriptomics (RNAseq) and metabolomics to look for signalling targets that we can inhibit as drug targets to further prevent MSC ageing while promoting MSC expansion.
The project is in collaboration with the industrial partner QKine who develop animal-product free growth factors for stem cells.

The predictive power of animal tests of new human drugs is poor, so we must find a new and better way to test the safety of new drugs. Our overall ambition is to develop new high throughput methods that advance preclinical testing using advanced human tissue culture with long term aims that will positively impact humans (with safer, more effective medicines), whilst replacing the use of animals in in vivo drug testing.
To achieve this, we will work with our partner, the charity Animal Free Research UK (AFRUK) to transform pharmaceutical testing of new drugs using novel optical spectroscopic methods to probe deep into cell-based constructs of animals’ organs (as a so-called “organ-on-chip). The new methodologies will be demonstrated within pharmacokinetic applications by exploring parameters involved in the metabolism of drugs in the liver (and their toxicity) and/or the adsorption of drugs either across the skin or within the GI tract. The ambition is to provide accurate models of the processes of drug uptake and metabolism in vitro, without using in vivo animal testing.
The project will provide you with experience of working at the interface between the biological sciences and physics/chemistry/engineering, with the opportunity to develop new spectroscopical/optical sensing methods and novel organ-on-chip cell culture techniques. The work will be aligned to the principles of AFRUK, and “organs” will be assembled as spheroid constructs in microfabricated devices using animal free culture methods.

Hydrogels belong to the most promising materials for cell-culture and tissue engineering. While biocompatibility and degradability of hydrogels are vital for use in cell-culture, mechanical properties have a significant impact on the cell differentiation. Therefore, hydrogel systems with well-controlled and tailorable mechanical properties are highly sought after. The present project will investigate the use of resilin in hydrogel fabrication as an environment for cell-growth with the ultimate goal of tissue engineering. Resilin has remarkable properties (as an elastomer it is literally the bee’s knees), which facilitates the introduction of a broad range of mechanical properties together with crosslinking chemistry, e.g. via carbon nitride in the visible light. Moreover, the project will make use of a modular approach to introduce further functions into the hydrogels in order to enhance cell-growth. Overall, the project will give rise to new robust ‘tuneable’ gels that will address many of the shortcomings of existing cell culture media and will represent realistic alternatives to animal derived materials in research.

We will investigate and analyse bioinks from the past 5 years and their performance as 3D bioprinted scaffolds, with specific regard on how viscoelasticity can be tuned and how this can affect stem cell behaviour. Based on this information I will develop a range of bioinks that enable 3D bioprinting of biocompatible scaffolds that utilise spatial organisation of bioinks with differing viscoelasticities. These stem cell seeded scaffolds will then be analysed to investigate the ability to simultaneously differentiate into different cell types based on mechanical properties alone within the one scaffold structure. Throughout the project, there may be possibilities to modify the bioinks to include filament like molecules or other components that disrupt the initial scaffold network to create additional highly aligned structural features to the scaffold. It will be important to develop appropriate protocols to maintain the best culture conditions for an eventual co-culture based scaffold, while considering the perfusion of culture media in terms of reaching particular spatial regions within the scaffold. This may illustrate the importance of having an additional perfusion network within the multi-bioink based scaffold and the need to analyse crosslinking methods and control. The visoelasticity of the scaffold will be assessed using rheology to investigate bulk stress relaxation, and other techniques such as AFM and Brillouin microscopy can be used to explore local mechanical properties. Stem cell proliferation, maintenance and differentiation will be analysed utilising cellular assays, fluorescence microscopy and viability techniques.

Tuberous sclerosis complex (TSC) is a rare genetic disease caused by mutations in the TSC1/2 genes. Mutation in these genes cause hyperactivity of the mammalian target of rapamycin (mTOR) pathway. Patients of TSC present with many symptoms; including focal lesions in the brain called ‘tubers’. These tubers are highly epileptogenic; leading to 80% of TSC patients developing severe epilepsy that does not respond to conventional antiepileptic drug. Uncontrolled epilepsy in TSC is incredibly dangerous as it can lead to sudden unexplained death (SUDEP), a major cause of death for TSC patients.
Current treatment option for TSC patients include mTOR inhibitors like everolimus. While everolimus is effective for many other symptoms of TSC, its efficacy for seizure reduction is low. The only remaining treatment option is surgical removal of the tubers; which can be effective but long-term success rate is variable. Thus, epilepsy in TSC remains an unmet clinical need and is a pressing priority for drug development studies in TSC.
We have identified a mitochondrial enzyme in lysine metabolism as potential new drug target for epilepsy in TSC. We intend to develop a new drug that targets this enzyme in the brain cells; while minimizing peripheral circulation of these drugs. Thus, this project aims to:
1. Engineer a mitochondrial-targeting compound targeting the lysine metabolic enzymes
2. Testing the efficacy of this bespoke compound on 3D-organoid model of the TSC patient’s brain
3. Measuring the pharmacokinetic properties of designed compound to ensure availability across the blood-brain barrier
In addition to the research aims above, the student will work with our partner organizations; the Tuberous Sclerosis Association (TSA) and Birmingham Children’s Hospital; to gain opportunity to work and interact with the TSC patients directly.

TBC

This project is of a highly interdisciplinary nature, at the interface of microengineering, biophysics and medicine, will focus on developing and engineering new methods for improved and accurate detection and assessment of skin cancers as well as understanding, monitoring and controlling the cellular and tissue responses to therapeutic treatments. Overall aim will be focused on development and clinical validation of advanced device for point-of-care diagnostics: ‘Novel Portable Technology for Early-stage Dermatological Cancer Diagnostics (DERMATech)’.
Skin cancer is one of the leading causes of morbidity and mortality worldwide, with high-complication rates. By engineering novel intelligent micronano-substrates combined with advanced spectroscopic techniques to non-invasively detect and quantify skin cancers at the point-of-care, this project will make important advancements in several fields, envisioned to lead to high-impact publications and patent protection. Designed as a portable, cost-effective platform, such novel technology will allow clinicians to rapidly assess skin at the point-of-need and detect the growth at the in-situ stages before it has become a full-blown skin cancer penetrated below the surface.
The multidisciplinary nature of this project will enable developing strong collaborations and integrating scientific findings with related projects as well as building broad skills-set that will maximize the knowledge and chances in making an impact on the world’s academic and industrial stages.
By diagnosing, monitoring and clinically evaluating patients and better understanding of underlying mechanisms of the diseased tissue and biofluids, the outcomes of this research will lay a platform towards revolutionizing the ways of improving the health and quality of life for millions of people worldwide.

GPCRs are the largest family of membrane proteins and most successful drug targets. Recently a group of metabolite sensing GPCRs has attracted interest in the treatment of metabolic disorders, including obesity and diabetes. In these disorders significant remodeling of adipose tissue occurs, leading to changes in the mechanical properties of the tissue. Although previous work has demonstrated that the function of many GPCRs is altered by mechanical stimuli, very little is known about how these mechanical changes in adipose affect the function of metabolite GPCRs. This project will use advanced microscopy techniques to first define how manipulation of metabolite GPCRs affects the mechanical properties of adipocytes. It will then establish how these changes in mechanical properties alter the signaling profiles of the receptors. Ultimately, this information will be used to establish better cell models and drug screening pipelines that properly account for changes in the mechanical properties of adipose tissue that occur in metabolic disorders.

The brain and its resident cells are nourished, sustained, and detoxified through the constant movement of fluid. This movement helps regulate the pressure within the skull, known as intracranial pressure (ICP), facilitated by complex pathways and cell barriers surrounding the brain. However, injuries to the brain, such as Traumatic Brain Injury (TBI) can cause long-term alterations in ICP, which can alter fluid movement and ultimately affect tissue structures – leading to cognitive changes in patients.
One important interaction to facilitate this fluid movement is the interface of two biological soft tissues: the brain and the meninges. The meninges are a tissue that surrounds the brain and spinal cord. Specifically, the meninges tissues have recently been shown to play an essential role in the homeostasis of the Central Nervous System immunity. Furthermore, this brain-meninges tissue interface is home to the CSF-brain barrier – an understudied cell barrier that may play an important role in neurodegenerative disease, particularly post-TBI. Therefore, this project aims to explore the interface between the brain and the meninges and how the resident cell barrier at this interface responds to alterations in fluid movement and tissue stiffness that mimic healthy and TBI conditions.

The immune system plays a key role in physiology and disease. Macrophages interact with stem cells to enable or prevent regeneration and modulate cancer progression. Macrophages acquire two major phenotypes (M1 and M2) that promote regeneration or inflammation, albeit a number of intermediate phenotypes have also been described at the interface with biomaterials. Here, we will develop multi-phasic in vitro 3D systems to investigate the relationship between macrophage polarization and mesenchymal stem cells. Unconventionally, we will develop living biomaterials – a novel generation of biomaterials that contain genetically engineered bacteria cells – that will be engineered to contain optogenetic bacteria that secrete cytokines in response to light and drive macrophage polarization into defined phenotypes.
The project in multidisciplinary and will develop living biomaterials to control macrophage polarization using light. By using 3D printing, we will develop multiphasic models that organize macrophages and stem cells and will investigate their interaction using light as an external trigger of the system. The models developed will be free of animal products, and will provide a step forward in incorporating and controlling the role of the immune system in advanced in vitro models.

Urological cancers account for 12% of all cancer-related deaths worldwide. Among the urological cancers, the incidence rate of testicular cancer has doubled in Europe and is increasing globally. Despite the sensitivity of testicular tumours to Cisplatin, the tumour develops resistance and recurs in 20-30% of patients, necessitating salvage treatment with conventional or high-dose therapies. Optimisation of targeted therapies is required to avoid tumour resistance and recurrence, thereby achieving more favourable clinical outcomes. However, treatment optimisation requires a preclinical model that accurately represents the complex microenvironment of urological cancer – such a model is yet to be developed. Current patient-derived xenograft models for testicular cancer are limited as they fail to accurately represent the stromal cells and tissues of the tumour microenvironment. To address this limitation, we will develop a novel hydrogel-based preclinical model that reflects 3D tissue architecture, host-tumour interaction, and reliable molecular diversity of the tumour, thereby providing a platform for optimising targeted therapies.

New materials and repair concepts for peripheral nerve injury are necessary to reduce it’s burden of devastating paralysis and sensory loss, with costs to the individual, their families, communities and national health systems. To address the neurobiology of the injury and improve recovery we look for someone to develop novel scaffold materials combined with commercial systems that release neurotrophic factors. This project aims to deliver new research to direct translation to nerve repair in a collaboration between School of Chemistry and the School of Molecular Biosciences. Due to the interdisciplinary nature of the project involves a wide range of techniques, from small molecule synthesis and characterization, to mechanical and electrical testing of new synthesized materials, cell biology and the unique chance of a placement in an industrial setting.

Bone is a complex tissue. When damaged, it can fully regenerate, regaining its initial structure and properties. Large-scale damage, however, can result in fibrous tissue ingrowth and skeletal deformity. To prevent this, bone defects can be filled with grafting material e.g. calcium phosphate ceramics that drive bone formation (osteoconduction) and trigger de novo bone formation (osteoinduction). This effect arises from localized delivery of orthophosphate ions (PO43-), and codelivery of pyrophosphate ions (P2O74-) significantly enhances this effect.
Identifying why the codelivery of the pyrophosphate ions enhances bone formation is challenging since no established method for simultaneously measuring pyrophosphate and orthophosphate ions in culture exists. We will use electrochemical sensors that can differentiate between orthophosphate and pyrophosphate ions to investigate the process in a novel organotypic model of bone formation that we have developed.
The student undertaking this project will be trained in tissue-culture, micro-XRF, microCT, SEM, immunofluorescence/confocal/light-sheet imaging, “omics” (genomics/proteomics/metabolomics) to understand cell differentiation/signalling in this system. They will work with industrial partners to develop inorganic assays to determine the balance between ortho- and pyrophosphate in solution, to validate the sensitivity electrochemical sensors. This technology will allow identification of optimal bone formation conditions, enabling the intelligent design of regenerative therapies.

Macrophages are essential to the immune system; they are vital for fighting infections and tissue repair after injury. Macrophages can adopt several different phenotypes in response to signals in their microenvironment. The two primary polarisation states for macrophages are M1 and M2. M1 macrophages are pro-inflammatory and most abundant in the early stages after tissue injury. The M1 macrophages then transition to M2 macrophages, which are anti-inflammatory and promote tissue repair. Failure of this transition to occur leads to impaired tissue repair.
Like all cells, Macrophages release extracellular vesicles (EVs), which can contain DNA, RNA, lipids and proteins and act as messengers between cells. Since the dynamic balance between macrophage states controls healing outcomes, regulating macrophage phenotype and enhancing M2 polarisation states may be a promising EV therapeutic strategy. M2 macrophages improve the proliferation and migration of mesenchymal stromal cells (MSCs), whose homing is vital to affect tissue healing at the site of injury, however, if their EVs carry the same potential is unexplored.
It is well known that macrophages respond to chemical stimuli but more recently it has been demonstrated that macrophages are mechanosensitive cells that can detect and react to biophysical stimuli. For example, they can sense and respond to their matrix stiffness, whereby increased ECM stiffness correlates with M1 polarization. Interestingly, it has recently been shown that the mechanically activated ion channel Piezo1 modulates macrophage polarisation and stiffness sensing. Furthermore, activation of the mechanosensitive ion channel Trek-1 is required for inflammasome activity in macrophages. However, it is unknown whether the polarisation state or mechano-stimulation of macrophages can regulate their EV secretion profiles or EV healing potency and this will be the focus of the current project.
In this project, we will use magnetic nanoparticles to remotely control the activation of these mechanosensitive ion channels. After activating these ion channels, we will use a fluorescence lifetime image microscopy (FLIM) based approach to identify M1 and M2 macrophages and collect their cultured media. EVs will be isolated, and their impact on MSC proliferation, migration, and differentiation status will also be assessed.

This PhD will involve working with Zimmer and Peacock Ltd who will provide exposure to industrial applications to help develop an integrated wearable device/biosensor for healthcare applications. This device will comprise electrochemical sensors for simultaneous non/microinvasively monitoring of multiple metabolites of body activities. The design may be a watch, patch, or ring.
In detail, this project will use microfabricated microneedles, microchannels to both sample interstitial fluid (ISF) and/or sweat and transport the fluid to biosensors for analysis. These analytes may include glucose (an important indicator for daily monitoring in diabetics), lactate (characteristic of septic shock diagnosis), and/or more complex analytes including cortisol.
We will conduct in vitro and in vivo tests on the manufactured device to verify its feasibility and measurement accuracy. Calibration-free protocols will be introduced by the inclusion of advanced calibration algorithms into the electronics’ firmware for prospective calibration of sensor data in real-time. In parallel, this PhD will develop a Fog/Cloud model based on Internet of Things (IoT) concepts to facilitate potential future applications of the developed sensor. The self-developed smartphone application can store and transmit data for users through cloud services and provide daily records for patients/clinical trials.
This PhD will also work with public and clinicians to understand how the wearable can best be developed and used for healthcare and/or health and wellbeing. The novel device will be tested in humans.