Bioprinting the gut microbiome for personalised medicine

Increasing evidence points to the gut microbiome determining an individual's health, with a change in the microbiome leading to diseases. New studies have shown the importance of the gut affecting the performance of other organs, such as the brain, kidney and bones, referred to as, for example, gut-brain axis. Moreover, the composition of the microbiome can interfere with drug efficacy, as recent evidence highlights depletion of drug by bacterial strains commonly found in the gut. Thus, the gut microbiome is a key player in both determining one's health and response to therapeutics. The project proposes to leverage bioprinting to develop more sustainable tissue engineered models of the gut that factors in the microbiome. Such microbiome-inclusive gut models will be a significant advancement over contemporary gut tissue models.

Bioprinting is an emerging technology in the field of tissue engineering that utilises additive manufacturing (AM) tools to develop more reproducible tissue models. AM encompasses a range of technologies that produce products in additive manner. It also offers digital precision, ability to design complex and bespoke structures, and, and can be integrated with other digital tools. AM tools widely used for bioprinting are extrusion-based techniques that require no or low-heat (< 40c) to process materials. These subsets of AM are ideal since they allow a range of tissue-relevant polymers and natural cells to be processed without damaging either material. Extrusion-based techniques are equipped with a multi-nozzle system that affords the user to develop multi-layered tissues, which are representative of natural tissue. Furthermore, as a digitalised tool, AM can be integrated with imaging modalities to print precise replicas of an individual's tissue, hence affording personalised grafts to be developed.

The project will exploit the advantages of bioprinters to develop gut tissue models that include the microbiome. Contemporary consensus is that three-dimensional (3D) tissue models are more representative than current 2D models. The process takes advantage of the digital precision afforded by bioprinting, as well as its ability to design complex and multi-layered tissue models. Both these features allow for reproducible bespoke models to be developed that will be an advancement on current tissue engineering approaches. Enhanced control over tissue size and architecture could ultimately yield artificial organs to be used for drug screening or eventual organ replacement. Of great importance, bioprinting has the potential to diminish the need for animal models, leading to more sustainable research, as well as reduce the waiting times for gut transplants.

Aspects of the project will involve:
- Develop a microbiome-inclusive gut tissue model using bioprinting. Explore materials that are compatible for both bioprinting and microbes
- Investigate pre-bioprinting process that will maximise cell viability, such as microbe-encapsulating methods
- Exploit the printer's multi-nozzle compatibilities to advance gut tissue engineering and develop multi-layered tissues
- Perform extensive characterisation techniques to understand the ideal printability characteristics
- Compare the performance of the bioprinted tissue models to traditional gut tissue models for high-throughput screening of drugs. In addition, assess whether the inclusion of the microbiome to the gut model will produce more representative drug performance.
- Replicate different gut disease states using bioprinting
- Establish a strategy for extending the bioprinting pipeline beyond bioprinting. The goal will be to develop an automated, high-throughput system with bioprinting being a key component

Pharmaceutical technologies underpin healthcare product development. Medicinal products are becoming increasingly complex, and while the next generation of research scientists in the life- and pharmaceutical sciences will require high competency in at least one scientific discipline, they will also need to be trained differently than the current generation. Future research leaders need to be equipped with the skills required to lead innovation and change, and to work in, and connect concepts across diverse scientific disciplines and environments. This CDT will train PhD scientists in cross-disciplinary areas central to the pharmaceutical, healthcare and life sciences sectors, whilst generating impactful research in these fields. The CDT outputs will benefit the pharmaceutical and healthcare sectors and will underpin EPSRC call priorities in the development of low molecular weight molecules and biologics into high value products.

Benefits of cohort research training: The CDT's most direct beneficiaries will be the graduates themselves. They will develop cross-disciplinary scientific knowledge and expertise, and receive comprehensive soft skills training. This will render them highly employable in R&D in the pharmaceutical, healthcare and wider life-sciences sectors, as is evidenced by the employment record in R&D intensive jobs of graduates from our predecessor CDTs. Our students will graduate into a supportive network of alumni, academic, and industrial scientists, aiding them to advance their professional careers.

Benefits to industry: The pharmaceutical sector is a key part of the UK economy, and for its future success and international competitiveness a skilled workforce is needed. In particular, it urgently needs scientists trained to develop medicines from emerging classes of advanced active molecules, which have formulation requirements that are very different from current drugs. The CDT will make a considerable impact by delivering a highly educated and skilled cohort of PhD graduates. Our industrial partners include big pharma, SMEs, CROs, CMOs, CMDOs and start-up incubators, ensuring that CDT training is informed by, and our students exposed to research drivers in, a wide cross-section of industry. Research projects in the CDT will be designed through a collaborative industry-academia innovation process, bringing direct benefits to the companies involved, and will help to accelerate adoption of new science and approaches in the medicines development. Benefit to industry will also be though potential generation of IP-protected inventions in e.g. formulation materials and/or excipients with specific functionalities, new classes of drug carriers/formulations or new in vitro disease models. Both universities have proven track records in IP generation and exploitation. Given the value added by the pharma industry to the UK economy ('development and manufacture of pharmaceuticals', contributes £15.7bn in GVA to the UK economy, and supports ~312,000 jobs), the economic impacts of high-level PhD training in this area are manifest.

Benefits to society: The CDT's research into the development of new medical products will, in the longer term, deliver potent new therapies for patients globally. In particular, the ability to translate new active molecules into medicines will realise their potential to transform patient treatments for a wide spectrum of diseases including those that are increasing in prevalence in our ageing population, such as cardiovascular (e.g. hypertension), oncology (e.g. blood cancers), and central nervous system (e.g. Alzheimer's) disorders. These new medicines will also have major economic benefits to the UK. The CDT will furthermore proactively undertake public engagement activities, and will also work with patient groups both to expose the public to our work and to foster excitement in those studying science at school and inspire the next generation of research scientists.