3D Models of Health and Disease
3D models of cancer - Tumoroids
We focus on engineering biomimetic models of multiple solid cancer types, including epithelial cancers and sarcomas. We aim to engineer the appropriate matrix composition, density and architecture and spatially segregate the cancer mass from the complex stroma. We can quantify invasion and interaction of the cancer into the engineered stroma.
- Tumouroid models to study ameloblastoma action
Dr Deniz Bakkalci is developing 3D tumour models for ameloblastoma to understand molecular mechanisms behind ameloblastoma-induced bone resorption. She has been involved in research-based internships within the Northern Institute for Cancer Research and has completed a project on cytogenetic characterization of childhood Acute Myeloid Leukaemia (AML).
- Discovering the bio-mechanical signatures of cancer cells
Auxtine Micalet is establishing novel Tumour Associated Stiffness Signatures (TASS) in engineered 3D cancer models and correlating them to different invasion patterns to predict the metastatic potential of cancer cells. Using an engineered biomimetic collagen-based 3D tumour model, she assesses the stiffness profile of the cancer mass while it invades the surrounding stroma using Atomic Force Microscopy (AFM).
- Novel drug treatment options for ameloblastoma
Dr Judith Pape works on studying molecular pathways involved in the early events of invasion for colorectal cancer. She also studied how vasculature within the tumour stroma is affected by the gradient of invasiveness of the cancer. Some of the work involved incorporating primary patient samples in the form of cancer associated fibroblasts (CAFs) into the tumouroids to study alterations on invasiveness, vasculature, and gene expression. Within this work, the angiogenic potential of CAFs was also tested within the model.
- Renal tumouroids to predict patient response to therapies
Dr Katerina Stamati works on kidney and prostate cancer tumouroids. Her lab work has contributed to the optimisation of the methods to expand cells (cancer, supporting cells) from patient tumours. She has worked on a feasibility study of patient-derived tumouroids for personalised cancer treatment. She also focuses on understanding how the 3D environment affects drug responses and how increasing the complexity of the tumour microenvironment affects cells and therapeutic interventions.
Connective tissue engineering
We develop 3D biomimetic in vitro collagen tissue models that mimic the structural and mechanical properties of native tissues. We are using these models to study cell-matrix interactions of healthy and hernia fibroblasts and to perform pre-clinical testing of commercial surgical meshes. We also develop inexpensive approaches for healthcare problems, such as an affordable, biomimetic surgical mesh for abdominal wall repair. We correlate the biological behaviour of cells to biomechanical properties of native tissues and engineered materials.
- Development of a novel mesh for abdominal wall repair
PhD student Alessandra Grillo (supervisors: Dr Kureshi, Prof. Mudera) is developing a new biocompatible mesh for abdominal wall repair, combining synthetic and natural components. She worked on the use of biomaterials for drug delivery to treat peripheral nerve injury as part of her MSc project.
- Pre-clinical hernia mesh testing
Tom Whitehead-Clarke is investigating pre-clinical hernia mesh testing. His project uses a 3D tissue model of the human rectus sheath to test several commercially available hernia meshes, with the aim of setting a gold-standard in the field of pre-clinical mesh testing. Tom is a specialty registrar in general surgery with interests in upper gastrointestinal surgery and complex hernia surgery.
Engineering the stem cell niche
Research in this area focuses on engineering specific elements of the stem cell niche. We have engineered several aspects of the stem cell niche, including the appropriate cytokine environment, the matrix composition and stiffness, and the effects of physiological hypoxia on stem cell populations.
- Skeletal stem cell biology
Rawiya Al Hosni has conducted research in stem cell niche engineering. The mesenchymal stem cell niche featured in her project are the periosteum and bone marrow. With regards to the periosteum derived cells, a periosteum derived growth factor cocktail was developed for successful maintenance of the stem cell characteristics and illustrated the ability to retain and improve cell potency, in vitro. A further 3D biomimetic model was developed using collagen type-1, incorporating the growth factor cocktail and periosteum derived cells. A biomimetic model was developed mimicking the native periosteum through cell localisation. This study has a potential in forming the basis for an ‘off the shelf’ periosteum mimetic in place of periosteal grafting, in vivo.
- Improving tissue integration and scaffold survival
Jasmine Ho (MRC and Rosetrees Trust funded PhD) is researching how to improve new blood vessel formation and growth in tissue engineered scaffold during the initial crucial stages of implantation. She will apply this knowledge towards improving tissue integration and survival of TE scaffolds in vivo. Her research shows that cells, particularly mesenchymal stromal/stem cells, when placed in a low oxygen environment, accelerate the growth of new blood vessels. She is looking to optimise the ideal oxygen conditions to yield the best pro-angiogenic environment without compromising cell viability. The findings will benefit tissue-engineered organ transplantation, organ regeneration and wound healing.
Musculoskeletal tissue engineering
- Peripheral Nerve Injury (PNI)
Philip Barrett (John Scales endowment funded PhD) is investigating an identified need in patients with peripheral nerve injury (PNI). There is evidence of sensorimotor dysfunction, affecting their daily activities. Proprioception is an integrated neuromuscular function, which is controlled by the physiology of intrafusal fibres. There is currently little evidence of how these fibres are affected in PNI and whether the regeneration and or/degeneration contributes to physiological function. This project is focused on the generation of an intrafusal skeletal muscle fibres in-vitro to provide a model for further investigation.
- Designing an anterior cruciate ligament graft to induce regeneration
Tania Choreno-Machain (Mexican government CONACyT-funded PhD) is developing a new bio composite scaffold for ligament tissue engineering. Her work involves the synthesis of a biopolymer to use as a coating for a synthetic ligament graft, plasma surface modification, the isolation of human ligament cells, and the use of a bioreactor for mechanical stimulation. Tania has been involved in clinical and research-based internships in Rheumatology and Immunology at the National Institute of Medical Sciences and Nutrition "Salvador Zubirán" (Mexico) and the Hôpital Cochin (Paris), a section of the Faculté de Médecine Paris-Descartes.
- 3D engineered biomaterials for musculoskeletal tissue regeneration
Ligaments are one of the most common tissues injured during sports, and they struggle to heal. The usual treatment is surgical reconstruction by an autograft. About 350,000 ACL reconstructive surgeries take place each year in the USA, making it one of the most common orthopaedic surgical procedures. Tissue engineered scaffolds for ligament regeneration may prove a promising alternative to reinstate ligament integrity after a complete rupture.
This research is to produce a new hybrid polymer fibrous scaffold for ligament tissue engineering. It explores the scaffold’s mechanical properties and ability to promote both immortalised mesenchymal stem cells (MSCs) and native ligament cells’ adhesion, proliferation, and extracellular matrix production in vitro.
The Centre for 3D Models of Health and Disease
Dr Deniz Bakkalci
- Gupta, P., Miller, A., Madhuri, T.K., Velliou, E., et al (2022). A Systematic Comparative Assessment of the Response of Ovarian Cancer Cells to the Chemotherapeutic Cisplatin in 3D Models of Various Structural and Biochemical Configurations-Does One Model Type Fit All? Cancers, 14 (5), 1274.
- Nyga, A., Stamati, K., Redondo, P.A., Cheema, U., et al. (2022). Renal tumouroids: challenges of manufacturing 3D cultures from patient derived primary cells. Journal of Cell Communication and Signaling.
- Pedersen, K., Vanhoestenberghe, A. & Heavey, S. (2022). Urgent action is required to increase sustainability in in vitro modelling. In vitro models.
- Barrett, P., Quick, T.J., Mudera, V. & Player, D.J. (2022). Neuregulin 1 Drives Morphological and Phenotypical Changes in C2C12 Myotubes: Towards De Novo Formation of Intrafusal Fibres In Vitro. Frontiers in Cell and Developmental Biology, 9, 760260.
- Pape, J., Emberton, M., & Cheema, U. (2021). 3D Cancer Models: The Need for a Complex Stroma, Compartmentalization and Stiffness. Front Bioeng Biotechnol, 9, 660502.
- Micalet, A., Moeendarbary, E. & Cheema, U. (2021). 3D In Vitro Models for Investigating the Role of Stiffness in Cancer Invasion. ACS Biomaterials Science and Engineering.
- Bakkalci, D., Jay, A., Pape, J., Cheema, U., et al. (2021). Bioengineering the ameloblastoma tumour to study its effect on bone nodule formation. Scientific Reports, 11, 24088.
- Grillo, A., Hyder, Z., Mudera, V. & Kureshi, A. (2021). In vitro characterisation of low-cost synthetic meshes intended for hernia repair in the UK. Hernia.
- Mudera, V., Whitehead-Clarke, T., Kureshi, A., et al. (2021). The experimental methodology and comparators used for in vivo hernia mesh testing: a 10-year scoping review. International journal of science and research methodology. Hernia.
- Ravi, B., Kapoor, M. & Player, D.J. (2020). Feasibility and reliability of a web-based smartphone application for joint position measurement. Journal of Rehabilitation Medicine, 0.
- Barrett, P., Quick, T.J., Mudera, V. & Player, D.J. (2020). Generating intrafusal skeletal muscle fibres in vitro: Current state of the art and future challenges. Journal of Tissue Engineering, 11.
- Wishart, G., Gupta, P., Schettino, G., Nisbet, A., & Velliou, E. (2021). 3D tissue models as tools for radiotherapy screening for pancreatic cancer. British Journal of Radiology.
- Mudera, V., Player, D.J. & Kureshi, A. (2019). Engineering of Collagen as a Functional Biomaterial. Comprehensive Biotechnology, Third Edition. Elsevier.