Light-driven biofabrication of 3D stem-cell chondrogenic tissue analogues

Articular cartilage (AC) defects are one of the major causes of immobility and poor quality of life for millions of individuals worldwide. Current medical therapies have proven to be insufficient for the long-term regeneration of AC defects. Alternatively, the application of bioprinting in tissue engineering (TE) allows for the fabrication of complex 3D constructs via the precise spatial deposition of multiple cells and biomaterials. When integrated with human pluripotent stem cells (hPSCs), bioprinting opens up the possibility to generate human chondroprogenitor-containing tissue substitutes that can then be transplanted into AC defects and produce cartilage to repair the defect. cartilage. Despite significant progress, the current differentiation protocols for hPSCs towards chondrocytes still present several challenges, including the high cost, inducing factor batch to batch variation and precise timing of administered growth factors and cellular receptor expression together with poor precision of pathway activation. Based on previous work [1], we hypothesise that through using optogenetics, which combines optical and genetic approaches to control cell signalling and hence phenotype, cell-signalling receptors that are critical for regulation of chondrogenesis can be replaced with engineered light sensitive receptors, allowing activation of signalling by specific light wavelengths. This will enable precision fine-tuning of differentiation in 3D bioprinted cell-laden hydrogels by light. If successful, this innovative approach would enable, for the first time, the dynamic manipulation of cell signalling pathways with high spatio-temporal precision.

There are numerous beneficiaries of this Advanced Biomedical Materials CDT. Firstly and of short term impact are the PhD students themselves. They will receive extensive research specific and professional/transferable skills training throughout the 4 years of the programme. They will have access to state of the art facilties and world leading academics, industry and clinicians. The training and potential placements are designed to maximise the impact of their research in terms of dissemination and movement of their research along the translation pathway.

Longer term benefits are that this distinct cohort will become the future UK Biomedical Materials leaders and be able to use their bespoke training and network within the cohort to collaborate on future worldwide funding opportunities and drive UK research in this area.

UK and international academics will benefit as they will gain the next generation of highly skilled postdoctoral researchers with knowledge and expertise not only in their specific research area but of industry, regulatory and clinical aspects.

UK and international industry will benefit - in the short term they will gain academic based research to further develop products and in the longer term have a pool of highly skilled graduates.

Clinicians will benefit from collaborative research and also the development of new and novel products to enhance the treatment of a variety of trauma and disease based needs from biomaterials.

The public will benefit as end users as patients that will have their quality of life improved from the products developed in the CDT and will be educated in novel technologies and materials to repair the human body. The UK economy will benefit from the reduced healthcare costs associated with the new and improved medical products developed in this CDT and subsequently from the trained graduates. The UK economy will also benefit from the increased revenue from medical sales products from the UK industrial partners we will be working with.

The impact of this CDT will be realised by direct academic, clinical and industrial engagement with the students allowing efficient and state of the at training and fast translation of developing products. Students will also be trained in knowledge exchange and will use these skills to disseminate their research to, and liaise with, the key stakeholders - the academic, industrial, clinical and public sectors. We will ensure widening participation routes are addressed in this CDT in order to include equality and diversity not only in our initial CDT student cohort but in future researcher generations to come.