Development and optimisation of novel bioprinting process for scalable production of tissue models using FRESH technique

Lead Research Organisation: University College London
Department Name: Biochemical Engineering


Context of Research
More than 5 million people in the UK are affected by Osteoarthritis (OA) every year, placing a multi-billion-pound burden on the local economy and the NHS. Despite more than 50 years of research, no effective drug is commercially available for OA. In vitro models are deemed an ethical alternative of the animal models - the most common model currently - in drug development but only simple model, typically with single tissue component, have been proposed due to their inherent scaffold related limitations, i.e. poor cell viability and instable cell phenotype. There is therefore an urgent unmet need for new technological platforms that enable reproducible and integrative human relevant OA in vitro models.

Aims and Objectives
Our aim is to develop biofabrication platform based on Freeform Reversible Embedding of Suspended Hydrogels (FRESH) technology, suitable for high throughput biomanufacturing to produce standardisable and translational human relevant OA joint models.
Specific objectives include:
1. Characterisation and optimisation of bioinks developed by ManchesterBIOGEL used for FRESH technique
2. Tailor platform for human chondrocytes and human osteoblasts engineering for mono- and co-cultures systems
3. Characterise tissue models developed in 2 for their quality and phenotype. Establish applicability of developed models to produce standardisable and translational human relevant OA joint models.

Potential application and Benefits
The clinical presentation of OA is extremely heterogeneous, with multiple subsets of patients. Further, the pathogenesis of early OA remains poorly understood, hampering the development of effective tools for early diagnosis and disease-modifying therapeutics. Given the limited availability of human tissue, numerous animal models have been utilised over the past 50 years to study disease onset and progression, as well as to test novel therapeutic interventions. Whilst in vivo models offer a reflection of the naturally-occurring whole-joint disease, the versatility of an in vitro system, and the desire to incorporate and exploit the potential of the 3R philosophy of refining, reducing and replacing the use of animals makes in vitro modelling of the disease highly desirable.

Research Methodology
The project partner Manchester Biogel (MBG) commercialises a family of synthetic hydrogel products for complex biological systems. This project explores use of these hydrogels to develop scalable, standardise chondrocytes and human osteoblasts engineering for mono- and co-cultures systems for AO models development.

A novel 3D fabrication technology, FRESH printing, will be explored in this project. This allows generation of complex and large tissue constructs. The student will characterise bioinks and optimised FRESH printing process using combination of computational and experimental approach. Once process is standardised, both on mono and co-culture cell printed models of osteoblast and chondrocytes will be developed. Cellular models will be tested for their survival and long-term differentiation, to establish tissue specific phenotypic development.

Alignment to EPSRC strategies and research areas
This project will critically contribute to two of the EPSRC healthcare technology challenges: "Developing Future Therapies" and "Optimising Treatment". It will provide fundamental tool (i.e. in vitro model) to identify future pharmacological therapy, in ethical and cost-effective manner, which will certainly lead to more optimal treatment. In the technological aspect, the project involves novel methods in "advanced materials" and "future manufacturing technologies" among the cross-cutting capabilities by providing a novel bioprinting platform.

Planned Impact

The CDT has a proven track record of delivering impact from its research and training activities and this will continue in the new Centre. The main types of impact relate to: (i) provision of highly skilled EngD and sPhD graduates; (ii) generation of intellectual property (IP) in support of collaborating companies or for spin-out company creation; (iii) knowledge exchange to the wider bioprocess-using industries; (iv) benefits to patients in terms of new and more cost effective medicines, and (v) benefits to the wider society via involvement in public engagement activities and impacts on policy.

With regard to training, provision of future bioindustry leaders is the primary output of the CDT and some 96% of previous EngD graduates have progressed to relevant bioindustry careers. These highly skilled individuals help catalyse private sector innovation and biomanufacturing activity. This is of enormous importance to capitalise on emerging markets, such as Advanced Therapy Medicinal Products (ATMPs), and to create new jobs and a skilled labour force to underpin economic growth. The CDT will deliver new, flexible on-line training modules on complex biological products manufacture that will be made available to the wider bioprocessing community. It will also provide researchers with opportunities for international company placements and cross-cohort training between UCL and SSPC via a new annual Summer School and Conference.

In terms of IP generation, each industry-collaborative EngD project will have direct impact on the industry sponsor in terms of new technology generation and improvements to existing processes or procedures. Where substantial IP is generated in EngD or sPhD programmes, this has the potential to lead to spin-out company creation and job creation with wider economic benefit. CDT research has already led to creation of a number of successful spin-out companies and licensing agreements. Once arising IP is protected the existing UCL and NIBRT post-experience training programmes provide opportunities for wider industrial dissemination and impact of CDT research and training materials.

CDT projects will address production of new ATMPs or improvements to the manufacture of the next generation of complex biological products that will directly benefit healthcare providers and patients. Examples arising from previous EngD projects have included engineered enzymes for greener pharmaceutical synthesis, novel bioprocess operations to reduce biopharmaceutical manufacturing costs and the translation of early stem cell therapies into clinical trials. In each case the individual researchers have been important champions of knowledge exchange to their collaborating companies.

Finally, in terms of wider public engagement and society, the CDT has achieved substantial impact via involvement of staff and researchers in activities with schools (e.g. STEMnet), presentations at science fairs (Big Bang, Cheltenham), delivery of high profile public lectures (Wellcome Trust, Royal Institution) as well as TV and radio presentations. The next generation of CDT researchers will receive new training on the principles of Responsible Innovation (RI) that will be embedded in their research and help inform their public engagement activities and impact on policy.


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