3D Printing elicits tremendous excitement from a broad variety of industry - it offers flexible, personalised and on demand scalable manufacture, affording the opportunity to create new products with geometrical / compositional freedoms and advanced functions that are not possible with traditional manufacturing practices. 3D Printing progresses rapidly: for polymerics, we have seen significant advances in our ability to be able to manufacture highly functional structures with high resolution projection through developments in projection micro stereolithography, multimaterial ink jet printing and two photon polymerisation. There have also been exciting advances in volumetric 3DP with the emergence of Computational Axial Lithography and more recent work such as 'xolo'. Alongside these advances there has also been developments in materials, e.g., in the emergence of '4D printing' using responsive polymers and machine learning / AI on 3DP is beginning to be incorporated into our understanding. The impact of these advances is significant, but 3D printing technology is reaching a tipping point where the multiple streams of effort (materials, design, process, product) must be brought together to overcome the barriers that prevent mass take up by industry, i.e., materials produced can often have poor performance and it is challenging to match them to specific processes, with few options available to change this. Industry in general have not found it easy to adopt this promising technology or exploit advanced functionality of materials or design, and this is particularly true in the biotech industries who we target in this programme grant - there is the will and the aspiration to adopt 3D printing but the challenges in going from concept to realisation are currently too steep. A key challenge stymying the adoption of 3D printing is the ability to go from product idea to product realisation: each step of the workflow (e.g., materials, design, process, product) has significant inter-dependent challenges that means only an integrated approach can ultimately be successful. Industry tells us that they need to go significantly beyond current understanding and that manufacturing products embedded with advanced functionality needs the capability to quickly, predictably, and reliably 'dial up' performance, to meet sector specific needs and specific advanced functionalities. In essence, we need to take a bottom-up, scientific approach to integrate materials, design and process to enable us to produce advanced functional products. It is therefore critical we overcome the challenges associated with identifying, selecting, and processing materials with 3DP in order to facilitate wider adoption of this pivotal manufacturing approach, particularly within the key UK sectors of the economy: regenerative medicine, pharmaceutical and biocatalysis. Our project will consider four Research Challenges (RCs): PRODUCT: How can we exploit 3D printing and advanced polymers to create smart 21st Century products ready for use across multiple sectors? MATERIALS: How can we create the materials that can enable control over advanced functionality / release, that are 3D Printable? DESIGN: How can we use computational / algorithmic approaches to support materials identification / product design? PROCESS: How can we integrate synthesis, screening and manufacturing processes to shorten the development and translation pipeline so that we can 'dial up' materials / properties? By integrating these challenges, and taking a holistic, overarching view on how to realise advanced, highly functional bespoke 3D printed products that have the potential to transform UK high value biotechnology fields and beyond.

Healthcare relies on medical devices, yet often these have significant risk of infection and failure. The medical device market is estimated to be just under US$500 billion, while US$25 billion is spent annually on treatment of chronic wounds. As our populations becomes older, our healthcare systems are also becoming stressed by multi-antibiotic resistance and viral outbreaks. For example, 50% of initial COVID-19 fatalities were due to secondary bacterial infections [Zhou et al. The Lancet, 2020]. Medical device failure rates of up to 20% burden our health service disproportionately through device centred infection, immune rejection, or both. The biomaterials that devices and external wound care products are made from significantly influence immune and healing responses and affect the outcome of infection. In the EPSRC Programme Grant "Next Generation Biomaterials Discovery", physical surface patterns (topographies) combined with novel polymers were found which both reduce bacterial biofilm formation and increase the immune acceptance of materials in vitro and in vivo in preclinical infection models. This provides a new paradigm for biomaterials used as implants and wound care products, where novel polymers can be topographically patterned to improved healing and acceptance using bio-instruction. To exploit these findings requires targeting to specific medical device environments and elucidation of the mechanism of action for translation by industry. This project will utilise 3D printing to manufacture ChemoTopoChips containing over a thousand polymer chemistry-topography combinations that allow the possible design space to be efficiently explored and mapped using semi-automated in-vitro measurements of host immune cell and infecting pathogen interactions individually and in co-culture. These ChemoTopoChips will allow a very high content of molecular information to be extracted from biomolecules secreted into the culture media (the secretome), those adsorbed to the surface (the biointerface) and their impact on both host cells and bacteria. The same fabrication approaches will be used to make devices for preclinical testing; in vivo information will be maximised using minimally invasive monitoring of infection and healing over time and detailed analysis of explants. These information streams will be merged using artificial intelligence (specifically machine learning) to build effective models of performance and provide mechanistic insight, allowing design of materials ready for translation as medical devices outside this project. After consultation with a wide range of clinicians we have chosen to target the following two devices: -Wound care products for chronic/non-healing wounds: dressings to reduce infection, induce immune-homeostasis and promote healing in chronic wounds that result in 7000 diabetes related amputations in the UK per year and cost the NHS £1bn a year to manage. -Implants requiring tissue integration but prone to fibrosis/adhesion and biofilm-associated infection: surgical meshes used for repair of hernias or pelvic organ prolapse commonly afflicting women after childbirth. The NHS undertakes 100k such operation each year with infection rates of up to 10%, plus foreign body response complications. The team assembled to exploit this opportunity has unique experience in the areas of biomaterials, artificial intelligence, additive manufacturing and in vitro and in vivo measurements of immune and bacterial responses to biomaterials. Facilities including the recently opened £100m Nottingham Biodiscovery Institute, the recently funded EPSRC £1m suite of high resolution/high throughput 3D printers and the unique £2.5m 3DOrbiSIMS Cat2 cryo-facility. These investments in Nottingham make this the only location in the world that is capable of undertaking this project. An Advisory Board of clinicians, industrial partners and leading academics will meet annually to provide input to the project.