Tissue Engineering and Regenerative Medicine

In conjunction with simple or multi-functional bioreactors to sustain or condition living systems ex vivo, it is possible to generate complex cell and tissue (organoid-like) systems either for studying normal healthy tissue development, differentiation, maintenance and repair - or what goes wrong in disease. This approach is particularly useful for studying human cell and tissue biology, as it reduces the need to use living organisms in research and carries major potential in molecular and cellular medicine for modelling disease and pioneering new therapies.

Within YBRI, the following human stem/progenitor cells and differentiating tissue systems are currently studied:

• Haematopoietic stem/progenitor cells (Kent, Bridge)
• Breast epithelial cells (Holding, Brackenbury)
• Mesenchymal stem/stromal cells (MSCs) for development of bone, cartilage and adipose tissues (Genever)
• Urothelial cells from bladder and ureter for reconstructing functional urinary tracts to building kidneys (Southgate)

The formation of complex 3D tissues offers powerful, experimental platforms for studying fundamental processes in tissue biology, including transcriptional regulators that drive tissue specificity and differentiation.

The cellular heterogeneity inherent within engineered tissue constructs lends itself to analysis using a range of state-of-the-art technological platforms available in the Bioscience Technology Facility, including 10X scRNA-sequencing and digital spatial profiling. New technology platforms such as “Phenospot” are being developed in Physics to study contextual cell response behaviours (Krauss, Johnson). In Engineering, machine learning tools, such as evolutionary algorithms are being applied to interrogate complex, biological systems captured by time lapse microscopy and transcriptomic datasets (Smith, Halliday, Mason), organic bioelectricity devives in wound healing (Higgins) and Raman spectroscopy for biomolecular fingerprinting (Hancock).

One application of normal tissue systems is for investigating pathogenic processes and establishing disease models. Examples are:

• Haematological malignancies (Kent, Bridge, Holding, Hitchcock)
• Urological diseases, from characterising benign uropathies using patient cells, to studying innate defence mechanisms induced following exposure to uropathogens in bladder, to identification of carcinogen-specific genomic signatures (JBU: Southgate, Baker, Mason)
• Osteoarthritis and skeletal disorders, including generating therapeutic products such as extracellular vesicles (Genever)

This activity is highly complementary to the work of experts in chemical biology such as Willems, Fascione, Spicer and Duhme-Klair, who are developing therapeutic or marker chemical tools that can be incorporated and tested functionally in tissue-specific in vitro models. Other approaches are being used to engineer nanoparticles to deliver regenerative cargoes to cells in vivo (Genever, Hancock, Kroger).

Biomaterials can be derived from either naturally-derived, nature-inspired, or fully synthetic precursors, with a wide variety of forms, structures, and functionalities. Ultimately, biomaterials may provide a more cost-effective 'off the shelf' approach than available by tissue engineering of cells or tissues on a per patient basis. Examples of biomaterials activity in YBRI includes:

• The synthesis of synthetic materials inspired by native tissues, that provide potent biochemical and topographical cues to growing cells (Spicer)
• Soft tissue acellular matrices (ACMs) derived by decellularisation of natural tissues to leave natural tissue scaffolds suitable, which are shown to be inherently tissue regenerative and useful in proof of concept studies for homologous tissue/organ repair (Southgate)
• Bone and cartilage matrices (Genever)

TERM interests within YBRI complement activities being undertaken at the other White Rose Universities; Leeds and Sheffield. Together we have established the ‘White Rose Biomaterials and Tissue Engineering Group' (BiTEG), which has grown to include researchers from across the Yorkshire region. The group provides a network to promote new ideas and collaborations and meets once a year in December to showcase novel findings.