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Showing impact case studies 1 to 4 of 4
Submitting institution
University of Durham
Unit of assessment
8 - Chemistry
Summary impact type
Technological
Is this case study continued from a case study submitted in 2014?
No

1. Summary of the impact

Durham Chemistry’s development of a continuous synthesis of graphene nanoplatelets provided the intellectual property for the formation of the spin-out Durham Graphene Science (2010) which was listed on FTSE AIM index in November 2013 as Applied Graphene Materials plc (AGM). The IPO valued the company at GBP26.2m. AGM has raised over GBP29.3m in venture capital funding, has 33 employees (2020 payroll, GBP2.20m) and has invested GBP2.85m in infrastructure to supply graphene for products developed with commercial partners including Halfords, SHD composites, Airbus Defence and Space, James Briggs Ltd, Century, [redacted], Infinite Composites, Alltimes Coatings, Blocksil and Applied Nano Surfaces.

2. Underpinning research

Graphene is a single layer of graphite (first isolated in 2004 using the Scotch tape method) and is a continuous network of hexagonally arranged carbon atoms which gives rise to high carrier mobility, exceptional mechanical strength and high thermal conductivity. However, in the early years, commercialisation was limited by material availability and difficulty associated with product formulation. Solvent exfoliation of graphite (Nature Nano. 2008, 3, 563) could achieve graphene concentrations up to 0.01 mg ml-1 in solvents such as N-methyl-pyrrolidone.

To address this challenge KSC, supervising EPSRC-funded PhD students Christopher Herron and Rebecca Edwards (2008-2015), devised a simple chemical vapour deposition/pyrolysis approach to synthesize graphene which was continuous, high yielding (gram scale) and easy to scale up [R1]. This methodology used a flow approach, assembling graphene from the simple molecular precursors; it had the added advantage that the by-products from the process were water-soluble sodium salts that were easily removed. Similarly, the process avoided the use of graphite which is difficult to remove from graphene products [R1,2]. This process was further developed to use solid sodium carbonate and ethanol spray in place of sodium ethoxide solutions [R2] and metal templates [R3]. The use of metal templates allowed the size and morphology of the graphene nanoplatelets to be controlled and tailored.

Following the successful synthesis of synthetically useful quantities of graphene [R1-3], Coleman has continued to innovate, elucidating the fundamental science and devising transformative preparative solutions for the generation of new graphene dispersions and nanocomposites suitable for applications [R4-6]. This is evidenced through the EPSRC funded project ‘Engineering innovation in graphene nanocomposites for consumer product and packaging applications’ (EP/K016784/1, GBP1,633,244) a collaboration between Durham University (DU), University of Sheffield, Applied Graphene Materials, Procter and Gamble and Dyson. This project explored the use of graphene in polymer composites for use in consumer products. Durham has been looking at controlling the interfacial interaction between graphene and polymer and how this impacts formulation and melt processing [R4-6]. This research and understanding have been developed further and used by AGM for the development of new dispersion and formulation technology for graphene nanoplatelets.

In recognition of the work on the continuous synthesis of graphene and the establishment of AGM, Coleman was awarded the Royal Society of Chemistry (RSC), Chemistry World Entrepreneur of the Year 2011 and the RSC Materials for Industry - Derek Birchall Award 2017 for creativity and excellence in the application of materials chemistry in industry. Durham University Business and Innovation Services and Coleman were awarded the Times Higher Education Research and Innovation Award 2012 for the scale-up and commercialisation of graphene fabrication technologies.

3. References to the research

Citations according to Web of Science: as of 08/12/20

[R1] C.R. Herron, K.S. Coleman, R.S. Edwards and B.G. Mendis, ‘Simple and scalable route for the bottom-up synthesis of few-layer graphene platelets and thin films’ J. Mater. Chem., 2011, 21, 3378–3383. DOI: 10.1039/c0jm03437a. [39 citations]

[R2] K. S. Coleman, ‘Production of graphene from metal alkoxide’, Patent WO2011012874A1, 3 February 2011. Assignee: Applied Graphene Materials. Priority Date: GB0913011A 27 July 2009. This patent is granted in Europe (EP2459484B1), Korea (KR101965882B1, KR101987390B1), Japan (JP5767218B2, JP5932090B2) and the USA (US9932227B2).

[R3] K. S. Coleman, ‘Process for producing graphene’, Patent WO2012172338A120 December 2012. Assignee: Applied Graphene Materials. Priority Date: GB201109962A, 14 June 2011. This patent is granted Europe (EP2720978B1), Korea (KR101717277B1), Japan (JP5860957B2) and the USA (US9440856B2).

[R4] S. C. Boothroyd, D. W. Johnson, M. P. Weir, C. D. Reynolds, J. M. Hart, A. J. Smith, N. Clarke, R. L. Thompson, and K. S. Coleman, ‘Controlled Structure Evolution of Graphene Networks in Polymer Composites’ Chem. Mater. 2018, 30, 1524−1531. DOI: 10.1021/acs.chemmater.7b04343. [13 citations]

[R5] M. P. Weir, D. W. Johnson, S. C. Boothroyd, R. C. Savage, R. L. Thompson, S. M. King, S. E. Rogers, K. S. Coleman, and N. Clarke, ‘Distortion of Chain Conformation and Reduced Entanglement in Polymer−Graphene Oxide Nanocomposites’ ACS Macro Lett. 2016, 5, 430−434. DOI: 10.1021/acsmacrolett.6b00100. [24 citations]

[R6] M. P. Weir, D. W. Johnson, S. C. Boothroyd, R. C. Savage, R. L. Thompson, Steven R. Parnell, A. J. Parnell, S. M. King, S. E. Rogers, K. S. Coleman, and N. Clarke, ’Extrinsic Wrinkling and Single Exfoliated Sheets of Graphene Oxide in Polymer Composites’. Chem. Mater. 2016, 28, 1698−1704. DOI: 10.1021/acs.chemmater.5b04502. [19 citations]

4. Details of the impact

The scalable route to graphene production [R1] was filed as patents by DU in 2009 and 2011 [R2,3]. To exploit this technology KSC formed the spinout company Durham Graphene Science (DGS) in 2010 (Company number 07330136) in collaboration with DU Business and Innovation Services who helped develop the business plan and patent strategy. Initial venture capital funding was secured from NorthStar Ventures (North East Proof of Concept Fund, GBP100K, 2010) and, subsequently, by IP Group as part of the North East Technology Fund (GBP600k, 2011 and GBP700k 2012). KSC was seconded from DU to the company for 2 days a week (2011–2014) as a Director and Chief Scientific Officer. DGS recruited an experienced management team and employees to establish a commercial-scale production facility at the Wilton Centre in Redcar, capable of producing graphene following the protocol developed at Durham [R1-3].

DGS was renamed to Applied Graphene Materials plc (AGM) [E1] and launched on the FTSE AIM stock market under the stock ticker AGM (IPO 20 November 2013). The IPO (through N+1 Singers) raised GBP11.0m in funding to allow expansion of infrastructure and increase staff to commercialise its graphene fabrication technology to the global market. This gave AGM an initial market capitalisation of GBP26.2m. Two additional fund raises of GBP8.5m (December 2015), GBP9.8m (October 2017) means AGM has raised over GBP29.3m (November 2013-2020) in funding from the financial markets (including institutional investors such as Eden Tree, Insight, Herald, Ruffer and Hargreaves Lansdown) to develop its graphene technology [E1]. In September 2017 AGM completed the construction of their new production facility for the new grade of material A-GNP 35 (to complement the original A-GNP10), which was fully operational in February 2018. AGM (2020) employs 33 people (80% listed as having a degree or higher-level qualification) based in Wilton, Redcar with a payroll of GBP2.20m (GBP17.44m 2014–2020). A full breakdown of funding, business engagements, income, salary costs, infrastructure investment and employees are provided in Table 1[E1].

**AGMp plc 2014 2015 2016 2017 2018 2019 2020
VC funding (GBPm) 11.0 8.5 - 9.8 - - -
Active Business engagements - 120 300 100 120 101 109
Income (GBPm) 00.2 0.10 0.25 0.27 0.20 0.12 0.08
Salary costs (GBPm) 1.12 2.61 2.91 2.65 2.85 3.10 2.20
Infrastructure & equipment investment (GBPm) 0.29 0.39 0.99 0.68 0.26 0.19 0.05
Employees (FTE) 30 33 42 45 44 43 33

Table 1: *Financial year runs 01 August to 31 July. Annual reports are published in Oct/Nov of the same year calendar year. VC funding is listed in year raised.

AGM’s customer base is seeing extensive growth in the coatings, composites, lubricants, adhesives and energy sectors in the short timeframe since production began (all products containing AGM manufactured graphene use original DU research and IPR [R1-3]). The business is currently focused on building business engagement for long-term partnerships and has 109 active business engagements (FY2020). Formulated products are supplied under the Genable® family, a fully characterised product platform specifically designed to a standard formulation to enable graphene technology to be delivered easily into existing manufacturing processes, enabling customers to consistently access the performance attributes of AGM’s A-GNP graphene nanoplatelets [E1].

Embedded image Coatings and Adhesives: In October 2019 Halfords (FY2019, turnover GBP938m) the UK's leading retailer of motoring, cycling and leisure products and services, with over 465 retail stores, launched a Graphene Primer containing an AGM graphene formulation [E1]. In the same period, James Briggs Ltd, JBL, (part of the Tetrosyl Group, the largest supplier of car care, parts and accessories in the UK, FY2018, turnover GBP144m) launched its Hycote graphene anti-corrosion primer, developed in collaboration with AGM [E2]. [redacted]. Since July 2020, Kent Europe GmbH in Duisberg, Germany have been launched Genable® graphene-based aerosol primers [E1]. Applied Nano Surfaces (Sweden) uses AGM formulations for its innovative graphene-fortified low friction coating Tricolit®-GO; [redacted] [E3].

In July 2019 Alltimes Coatings Ltd, a leading specialist in the supply and application of protective coatings for buildings, launched (Advanced Materials Show https://advancedmaterialsshow.com, with approximately 4,000 visitors) the Advantage Graphene liquid coating roofing system (with formulated AGM graphene), with significantly enhanced anti-corrosion performance and life expectancy, for industrial and commercial roofs [E4]. In July 2020 Blocksil Coatings launched a high-performance graphene anti-corrosion coating for industrial applications that has been approved by Avanti (the leading provider of Ka-band high-throughput satellite capacity in Europe, Middle East and Africa) for application on its large satellite communications dishes [E1,E4].

The coatings area is complemented by high-performance thermal paste adhesive materials. [redacted]. Since 2016 AGM has been working on the qualification of a thermal paste adhesive product TP300 and TP400 with Airbus Defence and Space. These novel epoxy adhesive systems exhibit high levels of thermal conductivity (3 and 6W m-1 K-1 respectively), combined with excellent mechanical, adhesive and outgassing performance [E5]

Embedded image Composites: In October 2016 Century Composites Ltd (40 years of manufacturing fishing rods) began sales of the Tornado Graphex sea rod range which uses carbon fibre with AGM graphene resin technology. AGM manufactured graphene now features in the new Century SGR (Stealth Graphene Reinforced) range. The graphene resin matrix used in the production of the carbon fibre prepreg carries the loadings generated on the rod and allows for the production of lighter rods with high strength and toughness. It is also used to minimises twist in the tip section which Century has called Generation 2 Anti-Twist Technology (Gen 2 AT-T) [E6].

Infinite Composites (October 2019) has successfully incorporated AGM's graphene technology into two resin systems for cryogenic pressure vessels being tested for use in multiple NASA spaceflight missions, including materials on the International Space Station Experiments (MISSE), Artemis, and Lunar Gateway [E7].

Embedded image In March 2017, SHD Composites Ltd launched a range of AGM graphene enhanced epoxy component prepreg resin system (MTC9800 and now MTC9810) for use in applications as varied as automotive components, sporting goods and artificial limbs. MTC9800 graphene-enhanced product has been used in the award-winning Sit-Ski project run as a technology demonstrator by the High Value Manufacturing Catapult. In March 2018, AGM announced a collaboration with Magna (largest automotive part manufacturer in North America with a turnover of GBP40.8bn, FY2018) and SHD Composites on the W Motors Fenyr SuperSport tailgate using MTC9810 [E8]. The Fenyr Supersport and Sit Ski were launched at JEC 2018 in Paris with approximately 40,000 visitors from over 100 countries [E8].

In May 2017 AGM launched their Structural Ink® technology platform to deposit AGM manufactured graphene resin on a structure in a targeted manner using 2D industrial inkjet printing. As part of the Nano Enhanced Aerospace Interiors (NEAT) project (MAA243, GBP149k), funded under the National Aerospace Technology Exploitation Programme (NATEP), AGM working with Composites Tooling Engineering Services (CTES), SHD Composites Ltd, Composites Evolution Ltd, Coventive Composites and GKN Aerospace (a multinational automotive and aerospace company with over GBP9bn revenue) demonstrated that graphene and Structural Ink® can enhance structural, fire, smoke and toxicity performance in composite parts for the aerospace industry. Several materials are currently undergoing field trials [E1,9].

Policy and Regulation: AGM have been actively involved in determining European health and safety regulation. AGM is the lead partner and founding member of a REACH consortium that will enable graphene to be used in commercial products in the European Union (EU). REACH requires all companies manufacturing or importing chemical substances into the EU in quantities of one tonne or more per year to register these substances with the European Chemicals Agency (ECHA). As part of this AGM (with KSC) and the consortium, have been identifying the risks associated with graphene manufacture, graphene dispersion and the use of graphene in commercial products [E10].

In summary, AGM and all products arose from the new method for producing graphene on a large scale invented at DU [R1,2,3]. AGM graphene materials are used by third parties who supply products to end-users and consequently detailed sales figures for some products are currently unavailable.

5. Sources to corroborate the impact

[E1] Applied Graphene Materials plc, (http://www.appliedgraphenematerials.com\), UK registered company 08708426; Launch announcement 20 November 2013 – RNS Number 4548T; Fundraise 18 December 2015 – RNS Number 4948J; Fundraise 08 January 2016 – RNS Number 3108L; Fundraise 30 October 2017 – RNS Number 9897U; AGM company reports (2014-2020) filed at UK Companies House (https://beta.companieshouse.gov.uk/company/08708426/filing\-history\) and published each year on the AGM website (https://www.appliedgraphenematerials.com/reports\-and\-presentations/\)

[E2] Graphene enhanced anti-corrosion aerosol primer paints: James Briggs Ltd and Halfords branded primer

[E3] Tricolit GO coating http://appliednanosurfaces.com/products/ans\-tricolit/; AGM Annual Report 2019, page 11

[E4] Alltimes Coatings (http://www.alltimescoatings.co.uk\); http://www.alltimescoatings.co.uk/our\-products/metal\-roof\-repair/, RNS announcement 09 July 2019 – RNS Number: 9642E. Blocksil (https://blocksil.co.uk/news\); AGM Annual Report 2020, page 12

[E5] Graphene adhesives: [redacted], AGM Annual Report 2019, page 13; Airbus partnership AGM Annual Report 2020, page 15

[E6] Century (http://www.century.uk\); Tornado Graphex sea fishing rods and the stealth graphene reinforced range now available widely (e.g http://www.centurycarp.co.uk/carp\-rods/century\-stealth/ and https://www.anglingdirect.co.uk/century\-tip\-tornado\-graphex\-sport\-rod, retailing at approximately GBP520 each), RNS announcement 14 October 2016 – RNS Number 5109M

[E7] Infinite Composites (www.infinitecomposites.com/\), RNS announcement 03 October 2019 – RNS Number 5887O; Graphene Info (https://www.graphene\-info.com/agm\-and\-infinite\-composites\-develop\-graphene\-composite\-material\-space\)

[E8] SHD Composites Ltd (https://shdcomposites.com\); SHD MT98100 used in tailgate of Fenyr cars (https://www.wmotors.ae/the\-fenyr\-supersport.php\), RNS announcement 08 March 2018 – RNS Number 045OH, and MTC9810 in sit-ski (https://hvm.catapult.org.uk/news/taking\-technology\-off\-piste/\) and http://www.jeccomposites.com/knowledge/international\-composites\-news/sit\-ski\-made\-graphene\-enhanced\-epoxy\-component\-prepreg; JEC 2018 Paris (http://www.jeccomposites.com/events/past\-events/jec\-world\-2018\), approximately 40,000 visitors from over 100 countries.

[E9] National Aerospace Technology Exploitation Programme (NATEP), RNS announcement 30 May 2019 – RNS Number 5324A.

[E10] Graphene: EC number: 801-282-5 | CAS number: 1034343-98-0 (https://echa.europa.eu/registration\-dossier/\-/registered\-dossier/24678/1\)

Submitting institution
University of Durham
Unit of assessment
8 - Chemistry
Summary impact type
Technological
Is this case study continued from a case study submitted in 2014?
Yes

1. Summary of the impact

Research from the strategic partnership between Procter and Gamble (P&G) and Durham Chemistry has " enabled unique and globally scalable innovation that has improved billions of consumers' lives around the world". We describe direct impact via consumer goods innovation of [REDACTED], research savings to P&G of [REDACTED], support/creation of ~150 jobs in the North East, and inward investment from the USA of [REDACTED]. P&G's preferred platform for skin testing new consumer products is now Durham's Alvetex® 3D cell culture technology. Alvetex®, marketed by ReproCell, has had **[REDACTED]**sales in period. Outreach activities impacting >6500 members of the public and featured on the BBC show "Inside Out" have arisen from the research.

2. Underpinning research

In 2010 Durham Sciences started to explore new ways of working strategically with industry to help build research impact. We chose to work with P&G, motivated by the fact that they are a global innovation-led company giving us the potential to impact their 5 billion worldwide customers. In the early relationship stages we shared research expertise (including [R1, 2, 3]) and ambitions to confirm that a strategic relationship would be of genuine benefit to both sides and to define early research projects building from Durham University (DU) Chemistry research. At the outset we adopted a "master agreement" covering all IP, exploitation and confidentiality aspects. This has meant that subsequent research programmes can be launched with minimal "activation barriers".

We have collaborated in diverse chemistry research areas including photobleaches, soil-surfactant interactions, surface-active polymers and molecules, enzyme stability, chelant design, anti-microbials, small molecular migration by experiment and theory, optical brighteners and hueing dyes, phase diagram prediction and lipid delivery systems.

We have also co-created a number of larger more collaborative projects involving Physics, Life Sciences, Computer Sciences and the Business School. Since 2010 the research grant portfolio has totalled around GBP23.6m (GBP7.6m/GBP11.5m/GBP4.5m industry/UK or EU government/University) and has involved around 70 University (25 Chemistry) academics and 50 industry researchers (across P&G sites in the United Kingdom (UK), United States of America (USA), Germany, Brussels and Singapore) working with 36 PDRAs and 44 PhD students. The research has been underpinned by several competitively won large grants including: CEMENT (GBP14m Regional Growth Fund project); MICSED (EU ITN GBP1m to Durham); and Molecular Migration (EPSRC GBP1m/industry GBP2m, Durham, Sheffield and Birmingham Universities with P&G, Mondelēz and Akzo).

We summarise below specific DU Chemistry research in soft matter, analytical, coordination and polymer chemistry that has led to the impacts described in Section 4.

Surface chemistry & characterisation: Prof. Colin Bain developed ellipsometry and Total Internal Reflectance (TIR) Raman Spectroscopy for measuring the absorption rates and quantity of surface-active species at solid-liquid interfaces (e.g. [R3] and GR/S15778). TIR-Raman spectroscopy offers 1-s time resolution and sub-monolayer sensitivity; Bain’s invention has been replicated by labs in Europe, Australia and the USA. These methods were re-applied in contract research funded by P&G to measure the uptake of new polymer additives on model surfaces in order to elucidate their mode of action in laundry applications. Bain also has long-term research interests in the properties of liquid jets and in flow and deposition on surfaces (e.g. [R4] and grants EP/E019323, N025245, H018913). The techniques and knowledge developed in these programmes were applied to the impact of jets on thin films of dishwasher formulations created with a slot-die coater, in further research funded by P&G.

Synthetic chemistry: Several of Durham's synthetic chemists have collaborated with P&G. Prof. Jon Steed's expertise in ligand design, coordination chemistry and crystallisation (e.g. EPSRC R013373) has been applied to the design of novel two-component CaCO3 crystallisation inhibitors for dishwashing applications. The work involved inhibitor design, structure function studies of inhibitor–metal interactions, combinatorial studies of efficacy, and development of rapid deposition test apparatus and is described in publication [R5] and a related patent [EP3456808A1].

3D cell growth and skin models: P&G have adopted DU’s novel skin test models as their preferred product development platform. The models derive from collaborative research between Cameron, Cooper and Przyborski (Durham Biosciences) that used emulsion templating to produce porous polystyrene materials [R1] that were developed into 3D cell culture scaffolds under EPSRC grant GR/T24043 and described in (e.g.) [R2]. Materials were subsequently optimised to produce thin membranes, tested for cell growth and the technology optimised for scale up and reproducibility. The product was commercialised as Alvetex®, and its early impact was described in a Chemistry REF2014 case.

Imaging and spectroscopy: Prof. Andrew Beeby's research interests lie in the area of photochemistry, time-resolved spectroscopy and imaging. Research methods in [R6] have been applied to study pigments in ancient manuscripts held in libraries across the UK, feeding an active outreach program. The same techniques have been applied to P&G product imaging challenges and transferred to P&G through purpose-built spectrometers that now form an integral part of their research testing portfolio.

3. References to the research

The references listed [and web of knowledge citations as of November 2020] are those that underpin the specific impacts described in Section 4.

R1. A. Barbetta, N. R. Cameron, and S. J. Cooper, "High internal phase emulsions (HIPEs) containing divinylbenzene and 4-vinylbenzyl chloride and the morphology of the resulting PolyHIPE materials", Chemical Communications, 2000, 221-222. DOI: 10.1039/A909060F [132 citations]

R2. M. Bokhari, R. J. Carnachan, S. A. Przyborski, and N. R. Cameron, "Emulsion-templated porous polymers as scaffolds for three dimensional cell culture: effect of synthesis parameters on scaffold formation and homogeneity", Journal of Materials Chemistry, 2007, 17, 4088-4094. DOI: 10.1039/B707499A. [79 citations]

R3. D. A. Woods, J. Petkov, and C. D. Bain, "Surfactant adsorption by total internal reflection Raman spectroscopy. Part III: Adsorption onto cellulose", Colloids Surfaces A: Physicochemical Engineering Aspects, 2011, 391, 10-18. DOI: 10.1016/j.colsurfa.2011.07.027 [19 citations]

R4. L. Yang, B. K. Kazmierski, S. D. Hoath, S. Jung, W.-K. Hsiao, Y. Wang, A. Berson, O. Harlen, N. Kapur, and C. D. Bain, "Determination of dynamic surface tension and viscosity of non-Newtonian fluids from drop oscillations", Physics of Fluids, 2014, 26, 113103. DOI: 10.1063/1.4901823 [22 citations]

R5. Y. Hong, N. Letzelter, J. S. O. Evans, D. S. Yufit, and J. W. Steed, "Phosphate-free inhibition of calcium carbonate dishwasher deposits", Crystal Growth Design, 2018, 18, 1526-1538. DOI: 10.1021/acs.cgd.7b01508 [1 citation]

R6. A. Beeby, L. Garner, D. Howell, and C. E. Nicholson, "There's more to reflectance spectroscopy than lux", Journal of the Institute of Conservation, 2018, 41, 142-153. DOI: 10.1080/19455224.2018.1463920.

The Durham-P&G team were awarded the Royal Society of Chemistry's 2015 " Teamwork in Innovation" award for " multidisciplinary, collaborative and high-impact research leading to product innovation" [E2], some of which is described in this document.

4. Details of the impact

Laundry formulations: Controlled polymer deposition onto different fabrics underpins the stain release properties of many laundry detergents. This improves efficacy, particularly at environmentally friendly low wash temperatures. In two collaborative projects with P&G scientists Dr Andrew Graydon and Dr Anju Booker, Prof. Bain used ellipsometry and TIR-Raman scattering (method in [R3]) to measure the adsorption of polymeric laundry additives onto mimics of synthetic fabrics and the effect of these additives on the adsorption of proteins and complex polysaccharides. The learning led to the introduction of new patented polymer technologies into single unit dose formulations (Ariel pods), a business with an estimated global value of **[REDACTED]**pa; in the attached evidence document [E1], P&G estimate the direct impact of this DU research as [REDACTED]. The insight gained into the lack of surface adsorption of some candidate molecules also shut down an industry-based research project which could not have succeeded twelve months ahead of schedule with an estimated saving of [REDACTED] [E1].

Cleaning and deposition in dishwashers: Automatic dishwashing is a [REDACTED] global business. The need for higher efficiency at lower washing temperatures to help reduce energy consumption drives continuous testing and product innovation in formulations and additives. Prof Bain's expertise in the properties of water jets, droplet splashing, spreading and flow on surfaces (e.g. [R4]) was used in two research projects with P&G scientists: Dr Nathalie Letzhelter and Dr Rachel Martin to help understand the dishwashing process. This has led to significant down-scaling of P&G test methods and the development of automated test rigs that reduce the testing time for new materials by a factor of five and allowed direct visualisation of the wash process providing an estimated [REDACTED] pa saving [E1]. P&G state that four new (confidential) technologies have been delivered to market that were qualified by the new methods. Total product sales are estimated at **[REDACTED]**and P&G have filed multiple patents in the area [E1]. Maximising "shine" by controlling deposition of CaCO3 and other soils is a second key consideration during dish washing. Work under the CEMENT project led to new combination additives [R5] (and patent EP3456808A1, Automatic dishwashing cleaning composition) and delivered a new experimental rig to P&G for quantifying soil build up. This has reduced formulation testing times from ~2 weeks to 1 day with consequent R&D savings of **[REDACTED]**pa [E1]. The scientific learnings continue to impact next-generation formulations.

Skin Models: DU Chemistry research into porous polymer scaffolds [R1, 2] created products for 3D cell growth which formed part of a Chemistry REF2014 impact case. The technology has since been bought by the Japanese Company Reprocell and is being sold as the Alvetex® range [E3]. Manufacture and supply of Alvetex® are led by Reprocell Europe within the UK at sites in Sedgefield and Glasgow. Sales in period are [REDACTED] [E4]. P&G, Reprocell and Durham University have entered a partnership for the full commercialisation of a novel model of human full thickness skin developed on the Alvetex® platform [E4]. This partnership enabled the technology-transfer to ReproCell, ensuring its on-going development. Alvetex® was selected by P&G as its preferred platform for robust and reproducible human skin models and they have invested ca [REDACTED] in Alvetex-reliant projects.

Embedded image

Fig1: (Clockwise) P&G products impacted, new shine ADW test rig and additives, Alvetex® polymers, a P&G/Durham PhD-student “imaging the gospels’’ and part of the dishwasher test system

Societal and other impacts: While harder to quantify, multiple additional impacts have arisen from the partnership:

  • North East jobs: Our Regional Growth Fund project CEMENT (2011–2016) created + secured 83+195=278 FTE-years (38+91=129 in REF period) in the NE economy within P&G and partner companies such as Peerless Systems [E5]; many of the positions have continued beyond the 2016 formal reporting cut-off. The total salary in-period is ~GBP3.2m. Our CEMENT collaboration enabled Peerless to develop then deliver four NE-built 30-pot automated washing systems to P&G sites (total cost GBP1.2m) which has revolutionised formulation testing protocols, saving P&G around [REDACTED] pa per instrument in terms of manpower, water and energy [E6].

  • Policy: Jeff Weedman (Global Business Development VP at P&G) spoke to US Governors in Washington in 2012 to influence US policy around entrepreneurship. He highlighted how UK universities (citing Durham in particular) were "more competitive, more aggressive, more forward looking, more business friendly" and better set up for interdisciplinary research [E7]. This thinking has helped secure significant subsequent US investment in UK innovation centres in the REF period, which P&G estimate has secured >20 FTE research jobs in the UK [E1]. Durham has received US inward investment of [REDACTED] into research in the period. EPSRC highlighted the partnership in a 2015 case study document [E7].

  • Anti-counterfeit and other devices: Prof Beeby’s spectroscopy expertise [R6] has enabled development of hand-held hyperspectral imaging cameras capable of in-field counterfeit package detection. This has developed into image recognition projects based in computer sciences valued at [REDACTED]. Scanning imaging short wave infrared (SWIR) spectrometers developed at Durham have now being replicated and used in P&G labs (GBP35k ea.) for in-house analysis of garment soil malodour sources, and hand-held devices destined for customer demonstrations of garment cleaning are under development.

  • Outreach spectroscopy and policy: Soft-matter related outreach activities have reached ~6500 members of the public pa in period via events at Durham Science Festival and Schools Science week staffed by P&G and Durham researchers [E8]. Beeby developed spectroscopic imaging methods to tackle P&G research challenges which have been reapplied in his research with historians [R6]. These have changed UK national policy around acceptable methods of artefact imaging in heritage science [E8]. Associated outreach work on "Imaging the Gospels"; featured on the 9/3/2020 BBC1 Inside/Out show filmed in Durham Chemistry [E8] and has been disseminated in over 20 lectures to groups including the Royal Society, Royal Academy, history groups and libraries.

We summarise with a quote from a P&G Senior Director [E1]: " ...the innovation partnership that Durham has established with P&G has enabled unique and globally scalable innovation that have improved billions of consumers' lives around the world directly supporting the economic, societal and health benefits that our product range enable".

5. Sources to corroborate the impact

E1. Letter from an Associate Director at P&G Newcastle to evidence commercially sensitive figures quoted in Section 4. Evidence was derived from a series of interviews held with P&G staff involved in the research described.

E2. Royal Society of Chemistry Teamwork in Innovation award 2015 citation.

E3. Alvetex® product brochure downloaded from https://resources.reprocell.com 29/1/2020 and 2014 REF impact case study.

E4. Testimonial from CEO of ReproCell evidencing Alvetex® sales.

E5. Summary document of jobs created under RGF funding as submitted to Department of Business Innovation and Skills as part of project audit and CEMENT project output/impact reports D1-D4 April 2014.

E6. P&G OPTIMAS internal document (confidential).

E7. Evidence on the impact of partnership on policy: EPSRC 2015 case study: https://epsrc.ukri.org/newsevents/casestudies/pandgepsrcpartnership/;The Roberts report; Wilson review, page 26: https://www.gov.uk/government/uploads/system/uploads/attachment\_data/file/32383/12\-610\-wilson\-review\-business\-university\-collaboration.pdf (2012); Presentation by P&G VP of Global Business Development to US state Governors documenting the importance of industry-academia strategic relationships ( https://www.c-span.org/video/?304528-3/creating-entrepreneurial-culture, particularly minutes 37 to 45 on the P&G-Durham relationship).

E8. Examples of Outreach around "Imaging the gospels" includes: https://eic.rsc.org/feature/the-monks-tales/3007345.article; https://www.soci.org/chemistry-and-industry/cni-data/2014/12/illuminating-the-past. BBC iplayer film broadcast nationally 9/3/2020 (filmed on 30/1/2020). Evidence of change in policy for document illumination safety limits. Evidence for science outreach numbers in annual reports of activities.

Submitting institution
University of Durham
Unit of assessment
8 - Chemistry
Summary impact type
Technological
Is this case study continued from a case study submitted in 2014?
No

1. Summary of the impact

Durham University spin-out, LightOx Ltd (Est: Aug-2016) is underpinned by interdisciplinary patented research spanning the fields of spectroscopy (fluorescence, emissive), organic and medicinal chemistry and biology. LightOx has raised over GBP2m in funding, currently employs 11 scientists, and is commercialising Durham research, to provide innovative technologies focussed on retinoid signalling pathways. They sell a range of functional probes, diagnostic imaging kits and new phototherapeutic drugs. LightOx was winner of the Bionow ‘Start-up of the Year’ and ‘Product of the Year’ (Nov-2018) categories. Recently established Nevrargenics Ltd (Est: Dec-2019), a sister company also based upon Durham retinoid chemistry, aims to develop drugs for neurodegenerative diseases. The value of LightOx is GBP9m following substantial third-party investment rounds, and Nevrargenics has a pre-investment valuation of GBP15m.

2. Underpinning research

The relationship between structure and function of synthetic retinoids has been extensively researched in Durham by Profs Andy Whiting and Ehmke Pohl [R1-4]. This research has led to the development of fluorescent retinoids, [R2] which have promise to change biological imaging, drug screening and subsequent drug design [R4]. Retinoids such as all-trans-retinoic acid (ATRA) are natural signalling molecules (mediating transcription events) that control diverse biological functions such as vision, cell proliferation/differentiation, growth of skin and bone tissue and immune function; retinoids have recently been identified as activators of tumour suppressor genes [R1,2]. Ongoing research at Durham [R1-6] is helping to map the complex and intricate retinoid signalling pathways and in so doing uncover new treatments for a range of conditions including cancers and neurodegenerative conditions [R6].

ATRA and its endogenous isomers are susceptible to photoisomerization and degradation because of their polyene structure, making their use as routine diagnostic reagents or future use as therapeutics problematic [R1]. In collaboration with LightOx, Durham University has designed and synthesised a range of synthetic (>300 fluorescent compounds, each offering unique physiological and photophysical properties), light stable ATRA analogues, such as EC23 [R1] (Fig.1) designed to exhibit strong, intrinsic, solvatochromic fluorescence [R5] whilst retaining the biological activity of the parent molecule, for example, maintaining reproducible stem cell differentiation [R2,3].

Other species, e.g., DC271 (Fig.1) have been synthetically evolved to act as functional probes allowing unprecedented imaging of cellular localisation using confocal fluorescence microscopy, enabling correlation between cellular target and biological activity [R4]. This has enabled Durham researchers to develop a highly reproducible in vitro fluorometric binding assay to characterise and quantify specific cellular binding targets and thereby unravel the intricate network of gene regulation controlled by retinoids [R5]. The small molecular size of the probes and high fidelity to the original ATRA structures is of particular importance and means that they avoid traditional problems associated with larger fluorescent tagged molecules (e.g. requiring tagging to a carrier molecule) [R1,2]. As direct retinoid mimics there is facile delivery into the cell (high cell permeability and diffusion rate), minimal disruption of key cell activity, and minimal off-target tissue accumulation [R4,5]. The retinoid mimics have been tested on a range of different cellular systems including keratinocytes, neuroblastoma and teratoma cells, all of which have successfully indicated localisation of the fluorescent retinoids. This has also been observed in living zebra fish [R5].

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Figure 1. Synthesised fluorescent retinoids and docking simulation in GOLD showing the binding poses of ATRA (natural retinoid) and DC271 synthetic analogue.

Recent Durham research has shown that further modified structures, e.g. DC324 can be used as photosensitisers to elicit the production of reactive oxygen species (direct photoactivation by UV-A or two photon absorption by near-IR 800 nm light) resulting in powerful cytotoxic activity [R5]. This offers many options for photodynamic therapy of which microbial infections, neoplasias and tumour treatment are currently being investigated by LightOx supported by Durham researchers.

Concurrent research is also targeting neurodegenerative disease drug development for conditions such as Alzheimer’s [R6]. The principal challenge has been to generate dual-acting retinoic acid receptor modulators (RAR-M) as the basis for a series of new rationally-designed and effective treatments [R6]. The research has identified a sub-nanomolar potency lead drug with high blood brain barrier penetration and ultra-low dose potential. The compound is currently being examined in relevant disease efficacy models.

3. References to the research

Citations according to Web of Science:

[R1] G. Clemens, K. R. Flower, A. P. Henderson, A. Whiting, S. A. Przyborski, M. Jimenez-Hernandez, F. Ball, P. Bassan, G. Cinque , P. Gardner, “The action of all-trans-retinoic acid (ATRA) and synthetic retinoid analogues (EC19 and EC23) on human pluripotent stem cells differentiation investigated using single cell infrared microspectroscopy” Mol. BioSyst., 2013, 9, 677-692. DOI: 10.1039/C3MB25505K. [19 citations]

[R2] G. Clemens, K. R. Flower, P. Gardner, A. P. Henderson, J. P. Knowles, T. B. Marder, A. Whiting, S. A. Przyborski, “Design and biological evaluation of synthetic retinoids: Probing length vs stability vs activity” Mol. BioSyst., 2013, 3124-3134. DOI: 10.1039/C3MB70273A [21]

[R3] V. B. Christie, D. J. Maltman, A. Whiting, T. B. Marder, S. A. Przyborski, “Retinoid supplementation of differentiating human neural progenitors and embryonic stem cells leads to enhanced neurogenesis in vitro ” J. Neurosci. Meth., 2010, 193, 239-245. DOI: 10.1016/j.jneumeth.2010.08.022. [19]

[R4] D. R. Chisholm, C. Tomlinson, G.-L. Zhou, C. Holden, V. Affleck, R. Lamb, K. Newling, P. Ashton, R. Valentine, C. Redfern, J. Erostyak, G. Makkai, C. A. Ambler, A. Whiting, E. Pohl, “Fluorescent retinoic acid analogues as probes for biochemical and intracellular characterization of retinoid signalling pathways” ACS Chem. Biol., 2019, 14(3), 369-377. DOI: 10.1021/acschembio.8b00916. [10]

[R5] D. R. Chisholm, R. Lamb, T. Pallett, V. Affleck, C. Holden, J. Marrison, P. O'Toole, P. D. Ashton, K. Newling, A. Steffen, A. K. Nelson, C. Mahler, R. Valentine, T. S. Blacker, A. J. Bain, J. Girkin, T. B. Marder, A. Whiting, C. A. Ambler, “Photoactivated cell-killing involving a low molecular weight, donor–acceptor diphenylacetylene” Chem. Sci., 2019, 10, 4673–4683. DOI: 10.1039/c9sc00199a. [4]

[R6] T. Khatib, D. R. Chisholm, A. Whiting, B. Platt, P. McCaffery, “Decay in retinoic acid signalling in varied models of Alzheimer disease and restoration of gene expression with novel receptor acid receptor ligands (RAR-Ms) to Regulate Protective Genes” Alzheimers Res. Ther., 2020, 73, 935-954; DOI: 10.3233/JAD-190931. [2]

4. Details of the impact

The impact of Durham’s synthetic retinoids research is being commercially developed via two Durham Chemistry spin-out companies: LightOx Ltd ( www.lightox.co.uk) which focuses on diagnostic tools and imaging technologies, with its major emphasis upon photodynamic therapy for treating surface, especially oral cancers; and Nevrargenics Ltd ( www.nevrargenics.com) a pharmaceutical start-up devising new medicines for neurodegenerative debilitating diseases that do not have current treatments such as Alzheimer's and Parkinson's.

LightOx (Est: Aug-2016) based upon patented Durham research [Patents: WO2008025965A2, WO2016055800, WO2017174999A1], markets synthetic retinoids developed by Durham Chemistry as tools for imaging, and assay development in the life science industries [R1-6, E1]. Its retinoid analogues enable cell imaging and bioactive molecule tracking using simple fluorescence and Raman spectroscopy techniques. LightOx has created a small molecule-receptor binding assay kit (see Fig.2). The kits have been purchased by >40 organisations worldwide spanning Brazil, USA, and Europe (sales of >GBP18k). Kits are now distributed globally by Merck Life sciences ( www.sigmaaldrich.com LightOxTM-range) along with an extended range of propriety retinoids through an exclusive 5 year deal (signed Dec-2018), current sales USD13.7k. Dr Wilke, Senior Product Manager for Emerging Chemical Synthesis at Sigma Millipore has worked closely with LightOx to develop the range and has indicated ‘excellent sales and repeat interest’ [E2].

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Figure 2. Small molecule receptor binding assay kit, DE360 co-imaged with MitoTracker® mitochondria stain. Cells fixed after 72 hours in 1µM DC360

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Figure 3. The LightOx light-box

Durham researchers have also developed a programmable light-box (Fig. 3) specifically tailored for use with these probes [R1-4] facilitating rapid diagnostic analysis. This is now also marketed on behalf of LightOx through Merck (released Aug-2019; 60-units commissioned, unit price GBP3,790). Following a successful RSC-run webinar the first production run of units has sold out [E2]. The unit is constructed to permit flexible configuration and provide defined and reproducible wavelength irradiation. The PhotoReact-365 nm version has been used in investigations of new anti-cancer treatments [R6]. A joint venture between LightOx and the Centre for Process Innovation (CPI) (National Healthcare Photonics Centre) [E3] led to the identification of several new lead candidates obtained by conjugating known HDAC inhibitors to a LightOx photosensitiser (Patent App:2019:GB1910239.1) [E1] creating a light activated therapeutic molecule for the treatment of pre-cancerous and early-stage oral cancer.

LightOx history: [E4]: Following creation and spin-out of the company from Durham University in Aug-2016, in Oct-2016 High Force Research Ltd (HFR) [E5] took an initial investment position of GBP180k and a follow-up tranche of GBP250k (Jan-2018 over 24 months) for a 30% shareholding in the Durham spin-out generating an initial company valuation of GBP1.4m. LightOx relocated from Biohub (Alderly Park, Cheshire) to its new business premises (Newcastle upon Tyne) in April-2019. The company has grown rapidly and currently employs 7 full-time scientists (biology/chemistry) and 4 part time (50-80%-FTE) managers as CEO/CTO/CSO. In addition, recruitment of other key personnel includes Steve Emery (Jun-2018) as non-executive director (former head of diligence AstraZeneca) to focus on business strategy, Tristan Sillars as CFO (Oct-2018), Amy Wright as Business Development Manager and Administrator (Jun-2019) and Nicola Emmett as Quality Control Manager (Jan-2020). The company has a salary outlay of GBP468k pa which would also equate to a further Gross Value Added (GVA) of ~GBP455k pa to the local economy [based upon Office of National Statistics data for the North East of England].

LightOx development: LightOx raised an additional GBP1.93m (July 2018-Jan 2020) from HFR, Meneldor & private investors [E6]. This has allowed LightOx to expand marketing of its biological probes, create prototype and commission the building of its light-box units and importantly for the long-term aspirations of the company to aggressively pursue its phototherapies for cancer [R5]. To date LightOx has invested over GBP1.51m in its technology and product development.

LightOx and Durham University has been widely recognised for its pioneering research and commercial development through the award of several business prizes and grants and has been highlighted in the national press (Daily Mail, Daily Express) [E7]. LightOx was twice silver medallist in the Medilink and Northern Powerhouse Alliance Business awards ‘Start-Up category’ (Feb/March-2018), a finalist in the Innovation Showcase at VentureFest (Nov-2018) and winner of the Bionow ‘Start-up of the Year’ and ‘Product of the Year’ (Nov-2018) categories. In addition, LightOx has been supporting its staff to become future scientific leaders and entrepreneurs; for example, Dr David Chisholm (a Durham Graduate), LightOx's Chemistry Team Leader was recently awarded "Promising technologist of the year" at the Bionow awards [E8].

**Nevrargenics: [**E9]: was founded in Dec-2019 (originally as RAR-M Therapeutics Ltd) to exploit specific neurodegenerative disease knowledge accumulated within Durham Chemistry [R1-3], LightOx, and Aberdeen University but outside LightOx’s primary business sector. Nevrargenics’ focus is primarily the development of neurodegenerative treatments based upon intellectual property described in two patents based on Durham research (WO2017174999 & WO2018029473) [E1]. The key lead candidate NVG0645, has already passed early-stage preclinical testing showing excellent PK/ADMET properties and is currently being taken through key aspects of: 1) target validation in advanced Alzheimer's cellular and animal models; 2) GMP scale-up and 3) preclinical toxicity testing in two animal models. The research has been presented under NDA to several major pharma companies who have acknowledged the significant commercial impact of the research, see support letter from Dr Fiona Marshall, VP Neuroscience and Head of UK Discovery Research at MSD [E10].

Durham University Research Impact Fund provided GBP10k for testing Nevrargenics lead compound DC645 in rats for bioavailability (Nov-2020). The results indicated exceptional efficacy even at exceptionally low dose levels, i.e., 0.02mg/kg. Further dosing studies are currently underway and additionally support this data. In Dec-2019 the Northern Accelerator for business support awarded a grant of GBP30k to Nevrargenics to recruit Dimitri Dimitriou (>30 years' experience in the pharmaceutical and biotech industry, https://ownyourventure.com/equitySim.html) to provide support raising ~GBP4-5m to pursue preclinical and Phase I/IIa work. A provisional valuation of GBP15m (ING Biotec Biotech valuation, Pharmaceuticals Western Europe) had been assigned to Nevrargenics pre-investment raise based upon the value proposition and 3rd party interests that would have seen the raise occur in March/April 2020. Unfortunately, the Covid-19 pandemic has significantly impacted progression of the fund raise and, in negotiation with core investors, it was agreed to postpone until the financial situation becomes more stable. Research and business development has, however, been on-going with a Chairman having been appointed; namely, James Bromhead ( https://www.linkedin.com/in/jabromhead/). A revised funding call based upon additional positive data is planned for Q1 2021. Following the several high-profile closures and numerous failures of many large pharma Alzheimer's and dementia programmes Nevrargenics aims to bring the first successful disease reversing drug for Alzheimer's to the market by 2025.

5. Sources to corroborate the impact

[E1] Patent filing history including patents.

[E2] Merck – (Sigma Millipore Europe) collaboration and engagement. Retinoid Screen Kits and components. See: https://www.sigmaaldrich.com (LightOx range) and https://www.merckmillipore.com/ (LightOx range). RSC webinar on PhotoReact-365: https://www.chemistryworld.com/webinars/illuminating-research-with-the-lightox-photoreact-365-benchtop-photoreactor/4012217.article.

[E3] Announcement of the joint venture between LightOx and the Centre for Process Innovation, the National Healthcare Photonics Centre. The identification of several new lead candidates as light activated therapeutic molecule for the treatment of pre-cancerous and early-stage oral cancer. See: https://optics.org/news/10/6/7).

[E4] LightOx Ltd: www.lightox.co.uk UK registered company 10308130, formed 2nd Aug 2016. Company House Reports provided. Company based on IPR from several DU patent families. Notch signalling for preparing a population of cells in autologous cell replacement therapy (WO2012035309-A1), Synthetic retinoids in cell killing (GB1613712.7), Fluorescent synthetic retinoids (WO2016055800).

[E5] https://www.highforceresearch.com/ UK registered company 02248615, formed 27 April 1988. Registered office address: Bowburn North Industrial Estate, Bowburn, Durham, DH6 5PF. Company reports. News of collaboration ( https://contactmagazine.co.uk/hotbed-for-growth-puts-businesses-on-fast-track-to-global-success/).

[E6] Meneldor ( https://meneldor.nl/) specifically managed by the founding partners Paul Lelieveld and Frans van Dalen.

[E7] Example press releases: https://www.insidermedia.com/insider/national/medilink-healthcare-business-awards-shortlist-unveiled?utm_source=southyorkshire_newsletter&utm_campaign=southyorkshire_news_tracker&utm_medium=business_article Alzheimer drug screening featured in many press releases such as 1) http://www.dailymail.co.uk/health/article-4063076/Do-Brussels-sprouts-hold-key-Alzheimer-s-pill-Festive-food-contains-nutrient-combats-dementia.html and http://www.express.co.uk/life-style/health/746739/Alzheimers-disease-dementia-brussels-sprouts-cure (All information is included in the article pack on awards and news).

[E8] November 2019 Dr David R. Chisholm "Promising technologist of the year" award at the Bionow annual awards https://bionow.co.uk/news/b5ddfadcd2cb62/diagnosis-companies-triumph-at-the-bionow-awards.

[E9] RAR-M Therapeutics Limited. Incorporated 18 December 2019. Name changed to Nevrargenics (trademarked from August 2020). UK registered company 12369627. Company House Reports provided.

[E10] MSD letter of support from Dr Fiona Marshall FMedSci, FRSC, FBPharm. VP Neuroscience and Head of UK Discovery Research for Merck Sharp & Dohme

Submitting institution
University of Durham
Unit of assessment
8 - Chemistry
Summary impact type
Technological
Is this case study continued from a case study submitted in 2014?
Yes

1. Summary of the impact

Durham Chemistry research has led to many widely-used crystallographic tools, diagnostic routines, software packages and enhanced instrumentation. Examples include an array of powerful commercial software packages – Olex2, Autochem, LabSafe, TOPAS and NAMI; new protein crystallisation screening kits ( Durham Screens); supramolecular organogelators commercialised for pharmaceutical crystallisation; and the pHeniX powder cryostat apparatus. Associated software sales total [REDACTED] and equipment sales [REDACTED]. We have delivered complementary crystallographic research-based services ([REDACTED]) and training to enable the next generation of industrial and academic chemists to save time and money through using state-of-the-art analytical techniques.

2. Underpinning research

Durham Chemistry has a long track record of research into the structure-property relationships of functional materials, and these are core activities for several of our departmental research groupings.

The application of crystallographic methods to solve industrial and academic problems is 100% reliant on access to modern computational software packages. Durham research has led to two of the globally most widely-used software packages for small molecule single crystal refinements and powder diffraction analysis. Under EPSRC funding (C536274, GBP940k), the JAKH group, informed by their X-ray crystallography expertise and research, designed and coded a comprehensive software package ( Olex2) of Python-integrated modules combined with an intuitive scientist-friendly GUI. This platform has allowed the development of many new algorithms to address specific research needs and these are distributed via the open-access smtbx small-molecule Python toolbox [R1]. In powder diffraction, JSOE has been integral in the development of the innovative TOPAS [R2] suite of software, and his research has led to the incorporation of multiple new data analysis methods therein. These include methods for parametric fitting of huge bodies of diffraction data (e.g., 1000 patterns simultaneously analysed) [R3], for analysing time-of-flight neutron and energy dispersive diffraction data, distortion-mode modelling of functional materials, molecular distortion modes, magnetic diffraction and stacking fault analysis. These methods are used extensively by both industry and academics, with four of these research papers being submitted to REF2021.

The process of producing single crystals for diffraction analysis is challenging, particularly in the field of protein crystallisation, and often perceived as a black box operation. Grant support from the Wellcome Trust (WT094759AIA; GBP147,719) allowed EP to develop a platform technology based upon Thermal Shift Assay data processing that automatically identifies the optimal conditions for protein crystallisation [R4]. This has been facilitated by the creation of bespoke software, NAMI, which can conduct automatic assessment of ThermoFluor assay data, generating melting points and phase transitions from fluorescence signals recorded as a function of temperature. The process has been optimised for high throughput operation in a 96-well format to suit industrial laboratory needs. Complementary research has also generated a series of protein stability screens (the Durham Screens). These accelerate research by providing an easy to follow protocol and an off-the-shelf kit to rapidly identify the optimal conditions to study protein-ligand interactions, thus enabling faster determination of key drug-target interactions [R4].

The control of small molecule crystallisation is also of tremendous importance. In particular, polymorph control of drug molecules allows the transformation of hard-to-control or amorphous active pharmaceutical ingredients (API) into readily-handled, predictable crystalline solids with appropriate physical properties. JWS has researched extensively into methods to induce specific polymorph crystallisation and has developed and published a series of supramolecular organogelators for pharmaceutical crystallization [e.g. R5], and contributed to research work underpinning new robotic crystallisation methods.

EPSRC-funded research into negative thermal expansion materials which contract on heating [e.g. R6] and on materials undergoing electronic phase transitions or light-induced phase transitions led to the design, prototyping and commercialisation (in 2003) of the pHeniX powder diffraction cryostat with Oxford Cryosystems ( https://www.oxcryo.com/product/phenix). Its optimised design incorporated several novel features permitting integration with a range of lab-based instruments, and enable analysis of multiple different sample types.

3. References to the research

Citations according to Web of Science.

[R1] L. J. Bourhis, O. V. Dolomanov, R. J. Gildea, J. A. K. Howard, H. Puschmann, “The anatomy of a comprehensive constrained, restrained refinement program for the modern computing environment-Olex2 dissected”, Acta. Cryst. A – Foundations and Advances 2015, 71, 59–75. DOI: 10.1107/S2053273314022207. [530 + 11,601 citations of a 2009 paper describing the software package with less detail on the algorithms developed.]

[R2] A. A. Coelho, J. S. O. Evans, I. R. Evans, A. Kern, S. Parsons, “The TOPAS symbolic computation system”, Powder Diffraction, 2011, 26, S22–S25. DOI: 10.1154/1.3661087. [150]

[R3] G. W. Stinton, J. S. O. Evans, “Parametric Rietveld refinement”, J. Appl. Cryst., 2007, 40, 87–95. DOI: 10.1107/S0021889806043275. [125]

[R4] M. K. Grøftehauge, N. R. Hajizadeh, M. R. Swann, E. Pohl, “Protein-ligand interactions investigated by thermal shift assays (TSA) and dual polarization interferometry (DPI).” Acta Cryst. 2015, D71, 36–44. DOI: 10.1107/S1399004714016617. [41]

[R5] J. A. Foster, K. K. Damodaran, A. Maurin, G. M. Day, H. P. G. Thompson, G. J. Cameron, J. Cuestra, J. W. Steed, “Pharmaceutical Polymorph Control in a Drug-Mimetic Supramolecular Gel” Chem. Sci., 2017, 8, 78–84. DOI: 10.1039/C6SC04126D. [56] [Front cover]

[R6] S. Allen, J. S. O. Evans, “The kinetics of oxygen migration in ZrWMoO8”, J. Mater. Chem., 2004, 14,151–156, RSC Hot Article. DOI: 10.1039/B310137A. [29].

4. Details of the impact

Durham research has helped create world-leading software for both single crystal and powder diffraction analysis (both sold commercially), delivered commercial crystallisation kits and diffraction hardware and has had direct impact on companies and the research community.

OlexSys software: EPSRC funding to JAKH enabled the development of Olex2 [R1], a software suite dedicated to solving, refining and visualising structures from single crystal diffraction data. Olex2 is commercialised via Durham Chemistry spinout OlexSys which employs 2 PhD-level developers (GBP700k economic impact in period) [E1], and which enables an open source version of the software to be provided to academia available free of charge. Olex2 has over 12,000 registered users and 800 new installations are registered per month. The software is launched once every two minutes (29k times per month) [E1] and we estimate that over 10,000 crystal structures are solved with Olex2 a year (currently ~45%, COD-data). The original paper describing the software [R1] has been cited >10,000 times in the REF period, demonstrating its impact on the global chemical community. OlexSys also provides bespoke commercial software to industry: Rigaku-Oxford Diffraction (ROD) sells a branded version of Olex2 with expanded functionality as part of their X-ray systems (unit cost >GBP300k, with an estimated [REDACTED] being assigned to the software). ROD have also contracted OlexSys to create an exclusive product AutoChem to provide automated, intelligent, real-time structure refinement during data collection as a core component of the CrysAlisPro control software which is supplied with all ROD diffractometers. The latest update, Autochem5.0 was commissioned in 2020 and will be released with all new diffractometers in 2021. Although sales figures have not been released, we understand >650 units have been installed worldwide (2014–2020), equating to [REDACTED] in assignable software sales.

OlexSys has used its expertise in research data management from structural research to launch “LabSafe” ( https://www.labsafe.org/index.html), a laboratory management package co-developed with Durham Chemistry (2015) that is used for safety assessment, purchasing, tracking and disposal of chemicals. It is now used across the whole of Durham Science Faculty (purchased for [REDACTED] 2017) it currently tracks 82,500 chemicals for 1500 users. Regensburg University have recently purchased the system (2019, [REDACTED]) and it is being evaluated by several major universities around the world [E1].

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Figure (Left to Right): Molecular Dimensions 96 well assay and NAMI analysis screenshot, TOPAS and Olex2 field dominance, and the pHeniX cryostat

Rietveld software: Powder-diffraction based research has also led to major developments in the TOPAS [R5] Rietveld package, with associated financial impact [E2]. TOPAS is now the most widely used software for Rietveld analysis by academic and (particularly) industrially users as evidenced by the >50% (and rising) share of global citations in the area shown in the figure and evidenced in [E3]. The similar market dominance to Olex2 is clear. Over [redacted] copies of the academic version of TOPAS have been sold in the REF period and around [redacted] upgrade licences (1st licence GBP1400; [REDACTED] total sales) [E2]. Bruker AXS sell a commercial version of the software (stand-alone industry price ~GBP25,000) approximately 50:50 to industry and academia, often as part of a much larger diffractometer purchase. While sales figures are commercially sensitive, Durham University estimate a similar number of sales in-period and total sales around [REDACTED]. We support the software through the Durham TOPAS wiki [E3] and discussion forum ( Topas - Topas Wiki (dur.ac.uk)), which has a vibrant and expanding community with >1,000 members from industries in the chemicals (e.g. Johnson Matthey, BASF), cement, pharmaceutical and mining sectors and academia.

Crystallisation kits: We have also exploited our structural research to provide several commercial solutions to the production of crystalline samples suitable for diffraction studies. EP has developed and commercialised a ThermoFluor kit for rapid Thermal Shift Analysis to optimise crystallisation conditions to study protein-small molecule interactions [R4]. He has also developed the associated NAMI software application (launched 2014, available from GitHub), which helps users automatically optimise conditions [E4]. NAMI has had >7,500 installations. The team has also devised three additional screening kits (pH, salt and osmolytes). Combined they provide a comprehensive indication of protein stability for a wide range of buffer and additive systems. The pH and salt kits were commercialised in 2017 by Molecular Dimensions (MD), followed in 2019 by the osmolytes screen [E5]. All are sold globally with steadily increasing sales reported: 2017; 29-kits=[REDACTED], 2018; 36 kits=[REDACTED], 2019; 65-kits=[REDACTED], 2020;139-kits=[REDACTED] [E5]. The growing influence of the kits has recently been extended using the new nanoDSF system, the accompanying video tutorial has >12,600 views (~17 views per day: Dec 2020) from around the world [E6].

JWS's research into gel crystallisation media for controlling pharmaceutical polymorphism [R5] has led to crystallisation kits being sold by TCI chemicals [E7] and more recently contributed to nanodroplet crystallisation techniques commercialised through SPT Labtech's mosquito liquid-handling robot and Indicatrix Crystallography Ltd [E7].

Powder cryostat sales: Impact through diffraction hardware includes the pHeniX powder cryostat co-developed with Oxford Cryosystems (OC) in 2003 and sold to industries, national facilities and academic institutions worldwide [R6, E7]. Around [REDACTED] units have been sold in the REF period [E8] at a list price of [REDACTED] ([REDACTED] total). OC confirm in E8 that: “ *without the research excellence of Durham University, we would not be manufacturing and selling these cooling devices as we are today.*” Their other technologies now use some of the ideas developed in the pHeniX.

Impacting industry: Our structural expertise has also impacted on industry through their exploitation of research consultancy work. Within period, single crystal and powder diffraction analyses with contract values over [REDACTED] were performed. For example, JSOE developed a novel automated analytical approach based on [R3] research methods for a Finnish mining company (via Stenman Minerals). The method was used by them to analyse >50,000 samples in the first month [E9]. We have also supported industrial users with solid state structure-related problems via Durham’s industry-funded solid state NMR service, helping 53 companies with work charged at [REDACTED]. JWS and JSOE have also acted as expert witnesses and advisors for pharmaceutical companies on several cases in involving multi-billion-dollar drugs, including major court cases in the US and Canada [E9].

Outreach and training: We place significant importance on outreach activities to maximise impact of our structural research through training the next generation of scientists. JSOE co-authored the 2019 text book on "Rietveld Refinement" [E3] and provides a suite of ~200 heavily-used online training examples [E10]. JSOE and IRE ran biennial training schools in Powder Diffraction and Rietveld Refinement in period ([REDACTED] turn over), training ~200 international PhD+ delegates (10% from industry) [E10]. They have delivered additional training in Australia (2015) and Sweden (2017). The Durham-based BCA X-Ray Single Crystal School trained >250 delegates. Olexsys staff have run over 44 international workshops in period reaching >3500 delegates, their YouTube Channel has >1200 subscribers; evidence for the effectiveness of these activities comes, in part, from the ensuing software citations (see figure).

5. Sources to corroborate the impact

[E1] Olex2 from OlexSys ( http://www.olexsys.org); UK registered company 07465154. Olex2 and Autochem: Oliver Presley, Program Marketing Manager (XRD), Agilent ( www.agilent.com). Labsafe: https://www.labsafe.org/index.html; CPI integration: https://www.uk-cpi.com/news/innovation-integrator-olexsys-labsafe

[E2] TOPAS: Bruker AXS’s, Head of Global Product Management XRD, and the owner of Coelhosoft have provided testimonials confirming JSOE’s contribution to TOPAS and sales figures. Data to support the figure citations is provided.

[E3] TOPAS software-associated links: TOPAS academic software link http://www.topas-academic.net/; Commercial offering via Bruker https://www.bruker.com/products/x-ray-diffraction-and-elemental-analysis/x-ray-diffraction/xrd-software/topas.html. Rietveld book: http://www.degruyter.com/books/978-3-11-045621-9.

[E4] The launch of the Durham screens is given in: https://www.lubio.ch/media/news/article/molecular-dimensions-presents-their-newest-protein-stability-screen-the-durham-osmolyte-screen/. Molecular Dimensions Ltd (Company No. 01794026) is a world-leading supplier of modern screens, reagents, other consumables and instrumentation for protein structure determination by X-ray crystallography. Their Head Quarters are in Newmarket, Cambridge, England. Details of the Durham Screens can be found on their website: http://www.moleculardimensions.com/products/durham-screens. Molecular Dimensions are owned by the American parent company Annatrace Products LLC who distribute the Durham screen products in the USA, Mexico, Brazil and Canada: https://www.anatrace.com/Workflow/CryoEM. The NAMI software is free to download and readily available on the Durham website – https://github.com/grofte/NAMI

[E5] Molecular Dimensions royalty statements copies provided by Research and Innovation Services - Durham University.

[E6] ( https://www.jove.com/video/58666/how-to-stabilize-protein-stability-screens-for-thermal-shift-assays) On-line statistics (30 December 2020, show 12,602 views, including from UK, Europe, US, China, Brazil etc. Locations of the views can be seen on the website).

[E7] TCI, SPT Labtech and indicatrix crystallography websites referencing JWS research contributions to crystallisation work.

[E8] Oxford Cryosystems testimonial on pHeniX cryostat (https://www.oxcryo.com/product/phenix\), brochures and sales statement.

[E9] Example open court records as expert witness. Testimonials from Stenman Minerals Ab, established 2011: website https://stenmanminerals.fi/etusivu/about-us/?lang=en.

[E10] Powder diffraction and Rietveld refinement school: website and delegate numbers. The International Union of Crystallography powder commission described it as a “school others should aspire to”. The problem-based learning example set for the powder school features many examples derived from Durham research to help train others in our methods. ( http://community.dur.ac.uk/john.evans/topas_workshop/pcg_workshop_menu.htm)

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