Bioactive Glass Microcarriers for the Expansion and Recovery of hMSCs for the Treatment of Pseudarthrosis Following Adult Spine Deformity Surgery
Pseudarthrosis is a failed solid bone fusion at a minimum follow-up of 6 months after surgery to correct adult spine deformity (ASD). It can lead to reduced quality of life, loss of correction and progression of deformity, and it represents the primary cause of 4-24% of all revision fusion surgeries. Cell therapy using the patients’ own mesenchymal stem cells (hMSCs) has shown considerable promise for non-healing bones, but producing the necessary cell dosage for successful treatment can be a real challenge. Although stirred-tank bioreactors containing off-the-shelf microcarriers have become the method of choice for the expansion of hMSCs, successful recovery of the cells from the microcarriers without sacrificing cell quality and yield can prove challenging.
The aim of this project therefore is to investigate a novel type of microcarriers fabricated from biodegradable glass, to be used for the scalable production of hMSCs for the treatment of pseudarthrosis after ASD surgery. Following their design, manufacture and extensive characterization, the bioactive glass microcarriers will be used in stirred-tank bioreactors for the expansion and subsequent non-enzymatic detachment of hMSCs. Process parameters (agitation, feeding regimes, degradation rate and harvest time), as well as final cell yields and hMSC quality will be compared against the use of commercial microcarriers and traditional cell detachment/harvest protocols employing proteolytic enzymes.
Translation and Manufacturing
Developing Novel Bioactive Materials for Bone Cancer Applications
Survival for bone cancer patients is poor despite the aggressive combined use of surgery, chemotherapy, and/or radiotherapy. Secondary or metastasis cancers are particularly prevalent in bone tissue locations. To improve clinical outcomes, novel therapeutic materials are required.
This interdisciplinary PhD project aims to develop and characterize new bioactive materials to improve clinical outcomes for patients suffering from bone cancer. Materials will developed to provide a control release of key metal ions to selectively induce tumour cell death and simultaneously stimulate new bone growth.
The project will build on previous studies undertaken within our group. The successful candidate will undertake a series of in-vitro studies to fully characterise these materials with the aim of developing and optimising materials for clinical applications. The project will involve working with cell lines and primary patient tumours.
Cell and Tissue Engineering, Cell Testing, Translation and Manufacturing
Bioprocess Development for Production of 3D Tissues to Underpin Creation of Engineered Meat
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.
Porcine Eye Model for the Development of Ocular Surface Treatments and Contact/Intraocular Lenses
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.
Recapitulating the Liver Tumour Microenvironment using Three Dimensional Culture of Human Epithelial, Endothelial, and Immune Cells.
Cancer therapy using immune checkpoint blockers (ICBs) which regulate 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.
Cell and Tissue Engineering, Drug Discovery
Development of Microengineered Integrated Noninvasive Diagnostic Technology for Traumatic Brain Injury (MINDTBI)
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 traumatic brain injury (TBI) 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 neurodiagnostics: ‘Microengineered Integrated Noninvasive Diagnostic Technology for Traumatic Brain Injury (MINDTBI)’.
By engineering novel intelligent micronano-cues combined with advanced spectroscopic techniques to non-invasively detect and quantify TBI at the point-of-care, this project will make important advancements in several fields, envisioned to lead to high-impact publications and patent protection. 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 TBI 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.
Development of Advanced EndoSpectroscopic Sensing (EndSpec-Sens) and Monitoring Device for Inflammatory Bowel Disease: From tissue and biofluid discovery, through early-stage diagnostics and onto personalized therapy
The PhD project is of a highly interdisciplinary nature, and lies at the interface between
biomedical engineering, biosciences and medicine. It will focus on developing and engineering
new methods for improved, accurate detection and assessment of Inflammatory Bowel Disease
(IBD) lesions and tissue healing as well as understanding, monitoring and controlling the cellular
and tissue responses to therapeutical treatments.
The research will include development and engineering of novel, integrated endoscopic and
Raman techniques and tailored microfluidic lab-on-a-chip to enable early-detection of IBD and
its disease activity, neoplastic changes and healing at nearly histological level and delivery of
successful stratification and tailored therapy to individual patients. By restoring and maintaining
diseased tissue and organs, the outcome of this research will lay a platform towards
revolutionizing the ways we improve the health and quality of life for millions of people
Cell and Tissue Engineering, Cell Sensing and Cell Testing, Translation and Manufacturing
Dynamic In Vitro Cornea Model for Designing Regenerative Medicine Approaches.
The cornea is the transparent window in front part of the eye. It is essential for refracting light to enter the eye signaling to the brain via specialized neurotransmitting cells. Damage to any part of this pathway could lead to blindness. Worldwide, the prevalence of blindness is approximately 39 million people. Of these, an estimated 15 million are sight-impaired or severely sight-impaired due to corneal opacity that may be secondary to several causes including infections, trauma, and inflammatory diseases. The incidence approximates 1.5-2.0 million cases of unilateral blindness/year. Persistent corneal ulceration may lead to perforation and the risk of permanent sight loss. Notably, the WHO states that globally, 80% of all visual impairment can be prevented or cured, and that new treatments for corneal blindness are a priority area. Although many approaches to cornea regeneration have been reported in the field, there is a lack of a fully functional, 3D model of the cornea which mimics the physical and biochemical properties of the cornea in which such technologies could be tested.
This project aims to build upon promising preliminary development of a novel photocurable material which we have demonstrated to match the physical and chemical properties of the natural cornea. This project will be based on developing a silk fibroin material system which incorporates tailored peptide hydrogels manufactured by Biogelx, in order to produce a novel bioink which will be used to 3D print an in vitro cornea model which could be used test tissue engineered constructs. Furthermore, the in vitro model will aim to provide the lacrimation and mechanical stresses experienced by the eye.
Cell-based Therapies for Liver Regeneration
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.
Engineered Mechanochemical Cancer Microenvironments
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.
Click here to view a short video clip about this project.
Engineering Encapsulation Materials and Methods to Preserve Organoids and Biopsy Material
We are seeking a highly motivated student to undertake a multidisciplinary project to solve the problem of how to preserve 3D cell and tissues to enable hospitals and laboratories to undertake personalize medicine studies. Increasingly, it is appreciated that fresh clinical samples or 3D organoids are valuable resources that enable researchers to explore personalized treatments for diseases such as cancers. This project will work in an academic setting, but in collaboration with the biotech company Atelerix to explore their technology around cell encapsulation https://www.atelerix.co.uk/ and how this might be optimized for 3D organoids and biopsy material. Personalised medicine requires that laboratories and hospitals share samples of precious growing cells and living tissues, but the shipment can present problems, including expense, cell viability and preservation of original phenotype. This PhD project will explore the key biophysical parameters needed for optimal cell preservation to keep cells, organoids and tissues viable during transit to improve our capabilities to perform research, including around personalized medicine.
Magnetic Hydrogels for Bone Tissue Engineering
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.
Click here to view a short video clip about this project.
From the Bee’s Knees to Biotechnology: Resilin-Based Hydrogels for Cell-Culture and Bioprinting
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.
Extracellular Matrix Controls Cell Behaviour by Modulating Attractant Diffusion
When embryos develop, when wounds heal, and during diseases such as cancer, cells move to new locations. This is almost never a random process – cell movement must be steered. The final shapes of embryos and tissues, and the outcomes of disease, completely depend on this cell movement. One of the most common steering processes is chemotaxis, in which cells move along gradients of attractive chemicals.
We have shown that cells do not passively respond to attractants. They participate – in particular, they shape gradients by removing and breaking down the attractants from their local vicinity. This creates two sources of information. First, it makes steep local gradients, because attractants are always scarcer near the cell and more plentiful further away. Second, the way new attractants diffuse to replace what the cells remove gives information about the local environment. This is the subject of this studentship.
We will use a highly multidisciplinary approach, combining computational modelling, biophysics and cell biology to understand how the interaction between attractants (for example chemokines) and the extracellular matrix affects diffusion of the attractants and thus the movement of the cells and the shape of the tissues.
The student will gain an unusually broad range of expertise, with training in all aspects from the modelling through to wet cell biology.
Bioengineering 3D Adipose Organoids for Type 2 Diabetes Drug Discovery
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.