2D Materials for Next Generation Healthcare Technologies (2D-Health)

Lead Research Organisation: University of Manchester
Department Name: School of Health Sciences

Abstract

This Programme Grant capitalise on the world-leading expertise and research infrastructure on graphene and 2D materials available at the University of Manchester (UoM) to develop future therapies and generate innovative healthcare technology platforms by ascertaining UK leadership in biotech and pharmaceutical development.

There is an increasing need to develop new innovative technologies for healthcare, digital services and other innovation with the vision to deliver health services in more efficient ways and with benefits to patients and taxpayers. The National Health Services (NHS) is under increasing financial pressure in recent years, mainly due to population growth and an increased demand on NHS services. In addition to that, a growing ageing population associated with increased prevalence of pathologies such as cardiovascular disease, dementias, cancer and diabetes significantly add to the cost of care in the NHS. Innovative solutions for development of future therapies that could respond to such unmet clinical needs, reduce the cost burden on the NHS and provide a more effective, safer and patient-centred care is highly needed now.

2D materials are one atom thick materials. The family of these flat crystals is very large and includes transition metal dichalcogenides, hexagonal boron nitride, and graphene among many others. Altogether, they cover a large range of properties (from conductive to insulating, from transparent to opaque, from mechanically stiff to compliant) that can be exploited for the creation of new devices and technologies with a wide range of applications. Various innovative G2D based materials and technologies have been pioneered at the University of Manchester such as the super-hydrophilic graphene oxide based membranes, 2D material water based inks for printable electronics, and graphene based printed technology for wireless wearable communication applications. These newly developed materials and technologies have great potential for use in biomedicine can be exploited for the design and engineering of novel healthcare technologies towards solutions or improvements of unmet clinical needs.

In the 2D-Health research programme, we formed a team of internationally renowned and highly esteemed multi-disciplinary researchers and some of the world-leaders in G2D research in order to utilise selected unique properties offered by G2D materials and technologies and to develop innovative solutions for specific unmet clinical needs in wound care and management (relevant to diabetes); tissue rehabilitation by electrical stimulation (relevant to dementia); cell therapeutics (relevant to cardiovascular disease); and immunotherapeutics (relevant to cancer).

This programme directly aligns to the EPSRC Healthcare Technologies priorities by aiming to develop future therapies in specific applications of unmet clinical need and draws on several cross-cutting capabilities: a) custom-design G2D materials into advanced materials under specifications aimed at a precise industry-driven use, exploring different chemical modification strategies; b) development of novel imaging and sensing technologies for tracking and monitoring therapeutic intervention; and c) develop G2D-based technologies through the preclinical stage for each of the application areas using relevant cellular and animal models. Strong partnership with industrial partners for rapid clinical translation and in collaboration with ethicists and regulators aims to ensure responsible and societally-acceptable innovations.

Planned Impact

Based on the ambitious objectives aimed at within the 2D-Health Programme and the broad interest in efforts to exploit 2D materials in socially-needed application areas (such as healthcare) we will generate a significant impact at the levels of scientific knowledge, end-user (industrial and clinical) engagement and the broader society. Moreover, we included public and end-user engagement as an integrated part of the programme deliverables (WorkPackage 5) that is dedicated to engagement and communication to maximise impact from the outcomes of 2D-Health programme.

Public engagement: Developing new biomedical technologies and new therapies from emerging materials, such as 2D nanomaterials, is expected to attract significant attention from the wider public, particularly patient groups who may benefit from the successful outcomes of the Programme. The PI, Co-Is and members of their team are actively involved with various national and international public engagement outlets to describe and showcase some of the most intriguing uses of nanomaterials in medicine.

End-user engagement: We are planning on communicating the knowledge and expertise generated in this research programme to the industrial and clinical partners and through them to their wider communities. The role and contribution of the four Industrial Champions in 2D-Heath will spearhead end-user involvement and maximise the potential to develop clinically translatable technologies. They will subsequently transfer and translate the technology further for commercialisation and up-scaling. We expect that translation of such innovative technology will contribute to UK job creation, economic growth and leadership in the UK Pharma and Biotech industrial landscape.

Ethics: The PI has a long track-record of preclinical work using in vivo models of disease. All experimental procedures will be authorised by the UK Home office and approved by University of Manchester Ethical Review Committee. The establishment of an Ethics & Regulatory Board chaired by Prof Bensaude-Vincent (Sorbonne) a member of the CNRS (French National Centre for Scientific Research) Ethics Committee will guarantee integration of ethical issues within the Management structure of 2D-Health, so that all ethical matters raised during the course of the Programme to be timely addressed.

Regulation and Responsible innovation: Development of novel biomedical technologies and new therapies based on advanced materials is of great interest for regulators who want to ensure that the science and technology generated is in the public interest and is not detrimental to the environment and public health. Experts from the Medicines and Healthcare products Regulatory Agency (MHRA), Food and Drug Administration (FDA) and European Medicines Agency (EMA) will be invited to participate within the Management structures and Advisory Bodies of 2D-Health at a very early stage of the programme to secure incorporation of their advice in the vision/direction of the Programme.

Research project design: It is expected that the size of the market for products incorporating engineered nanomaterials, including 2D materials, will grow exponentially as more industrial applications adopt them. On the forefront of such developments and within that supply chain will be some of our SME commercial partners (Graphenea, 2DTech) that up-scale processes for 2D material production. These industries will also be beneficiaries of the outcomes of this programme that will allow them to de-risk their business by know-how in production of 2D materials at biological and/or clinical grade.

Publications

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Description Following the evolution and progress of the research activities in the last year and in combination with the constructive feedback from the Advisory Board, the 2D-Health Programme has been consolidated to consist of three pillar technologies, designated as Research Themes. Each of them aims to translate the unique features of graphene-based 2D materials in a specific biomedical application area. This project is just over halfway-through and has several important key findings:
1) Research Theme I: development of graphene-based membranes with limited swelling. We have developed a graphene-based smart membrane which responds to an external electric potential and thus controls the water transport through the membrane. Graphene is capable of forming a tuneable filter or even a perfect barrier when dealing with liquids and gases. New 'smart' membranes developed using an inexpensive form of graphene called graphene oxide, have been demonstrated to allow precise control of water flow by using an electrical current. The membranes can even be used to completely block water from passing through when required. These findings mimic several biological processes and hence have the potential to develop artificial biological systems and advanced nanofluidic devices for various applications.
We have additionally developed a silver-impregnated graphene oxide coating for antimicrobial applications. In vitro antibacterial analyses with E. coli and S. aureus bacteria show that the bactericidal efficacy of the graphene oxide-based coatings last for an extended time (minimum of five days). Developing safe and long-lasting antimicrobial coatings has enormous significance in the social and industrial sectors. We have developed a graphene-based coating that can be potentially used for wound dressing and coating layer on implant surfaces to reduce the bacterial infection. Our study confirms that the developed graphene coating is even efficient in killing bacteria for an extended period of time due to its slow and efficient release of antimicrobial agents. The slow and efficient release of antimicrobial agents from graphene-based coating could potentially avoid the overdose of antimicrobial agents currently being used in the commercially available bandages and implants.
2) Research Theme II: development of biocompatible graphene-based inks. Investigation of graphene exfoliation mechanisms, using positively charged pyrene derivatives, has enabled us to produce positively charged graphene dispersions in water for biomedical applications. We are able to compare its properties and interactions with existing negatively charged graphene dispersions. We have developed synthetic tools to make stabilisers that can be used to prepare graphene from simple graphite, with a higher exfoliation efficiency. The stabilisers confer graphene water solubility so that they can be used in in-vivo systems. We were able to separate the graphene dispersion according to size using cascade centrifugation and ongoing work is investigating their bio-compatibility. The particles can be functionalised with radio-active indium-111, which is essential for their imaging in vivo, thus enabling the tissue distribution of graphene oxide sheets to be determined. The functionalisation route is particularly novel because it avoids the use of chelating agents that are normally required to bind radiometals (such as indium).
3) Research Theme III: molecular engineering of graphene oxide with peptides. The possibility of binding protein molecules to graphene oxide is very promising for future clinical applications. We have developed a much better understanding of how innate immune cells, in particular dendritic cells, respond to different sizes and doses of graphene oxide sheets in vitro. We have also begun to understand how graphene influences the ability of such innate immune cells to activate T cells. We have revealed that graphene and 2D materials can be safely administered in living animals (under anaesthesia) for pharmacological purposes. This project has allowed the complex formation between graphene oxide sheets and protein-based biomolecules to be explored as therapeutic agents against cancer. We have moved into the establishment of three mouse models of cancer (melanoma and glioblastoma) to be used as the preclinical disease models of preference for the assessment of the technologies developed. Therapeutic efficacy in more cancer models will be studied in the remaining part of the Programme Grant in this Theme.
Exploitation Route Based on what is described above, these Key Findings can be taken forward in the following directions:
1) The achievement of electrical control of water flow through membranes is a step change because of its similarity to several biological processes where the primary stimuli are electrical signals. Controlled water transport is a key for renal water conservation, regulation of body temperature and digestion. The reported electrical control of water transport through graphene membranes, therefore, opens a new dimension in developing artificial biological systems and advanced nanofluidic devices for various applications. Further extended research is needed to explore this research area further.

2) Currently, titanium-based implants suffer from deteriorating effectiveness over the post-surgical period due to bacterial infections. This leads to the removal of the prosthetics, creating both health and financial burdens. Our developments provide a robust technology to improve the life expectancy of the titanium-based implants. Our findings on stable and long-lasting antimicrobial activity of silver-impregnated graphene oxide allow its use in several applications such as wound dressings and coating for implants to reduce infections. Further research regarding cell toxicity and antimicrobial activity towards specific microbes are required before the clinical trials. The involvement of our Industrial Partners, Smith & Nephew, will guarantee that the outcomes of this research will be evaluated and taken forward by this industrial user.

3) Possible biological applications based on our inks, as their charge can be selected ad-hoc and they are biocompatible. We are also able to add different functionalities to graphene by synthesizing pyrene derivatives with different functional groups. Our graphene dispersions are currently being tested for biological studies. This will lead to a better understanding of the cellular uptake and intracellular transport mechanisms. Moreover, size-dependant biocompatibility and pharmacokinetic studies can be performed.

4) By showing that these materials will be safe for human use. Our novel method of radio-labelling graphene oxide will enable us, and others, to track the in-vivo distribution and fate of graphene-oxide. This will allow a better understanding of the pharmacokinetic action of GO and derivatives.

5) Others could replicate and use the stabilised graphene preparations.

6) They provide a foundation for ongoing and future work addressing how graphene alters innate immune cell and T cell activation and function in-vivo, in particular in a cancer context.
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description 2D-Heath Mini Symposium 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Study participants or study members
Results and Impact The First 2D-Health Mini Symposium took place in London on the 24th of April 2018.

It was a very nice event and the first opportunity to have in the same place all the people involved in this project, PIs, Postdocs and the members of the Advisory Board. In these event the leaders of the four Research Themes gave an introductory presentation about the topics of the research focusing on the state of the art of the technologies studied. Three keynote speakers gave spoke about three important aspects of the biomedical technologies:

- Prof Michelle Bradbury from the Memorial Sloan Kettering Cancer Center of New York talked about her experience of Clinical Translation of Nanotechnology
- Dr Hannah Maslen from the University of Oxford gave her view on the ethics of the Nanotechnology
- Dr Daniel Chew from Galavni Bioelectronics gave his talk focusing on the industrial front of the Graphene based technologies.
Year(s) Of Engagement Activity 2018,2019
URL http://2d-health.com/2d-health-mini-symposium-2018/
 
Description 2D-Heath Research Ethics Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact The 2D Health Research Ethics workshop was held on 21st January 2020 at the National Graphene Institute, Manchester. The event was open to all University of Manchester staff and postgraduate student. We also had attendees from the University of Liverpool. We had an excellent line-up of speakers who covered topics such as: Embedding Ethics and Society in Research Practice, Principles of Research Ethics, Dual-use Research and Export Controls, Bioethics, Ethics of Animal Research and Ethics and Regulatory Pathways. The event was a great success and we had excellent feedback from the attendees.
Year(s) Of Engagement Activity 2020
URL http://2d-health.com/researchethicsworkshop/
 
Description ACS on Campus 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact ACS on Campus, the American Chemical Society's flagship outreach program, began in 2010 with events at a handful of universities. Today, we have been to hundreds of institutions around the world and continue to grow globally. We bring the leaders in chemistry, publishing, science communication, and career development to your institution's doorstep.
Year(s) Of Engagement Activity 2018
URL https://acsoncampus.acs.org/events/university-of-manchester/
 
Description Bluedot Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Joining the Bluedot festival for outreach activity was great fun experience, even compared to other outreach activities. There was variety of people coming to enjoy the festival, from families with toddlers to many others who were genuinely interested in development of science and technology. Lots of people showed interest in graphene and its possible applications, including A-level student couples who seemed to know much about graphene already, a few University of Manchester Alumni, and some people working in industry wanting to know how graphene can be used in their specific field. Many of adults already heard of graphene and its wonderful properties before and wanted to know more about possible applications and found it interesting to hear its possible applications in health applications and very much impressed with its potential uses in drug delivery, bio-imaging, sensors, etc. Moreover, the festival offered much more for us participants to enjoy, including many talks, exhibitions and music stages to go around to pick and listen. It was a weekend full of excitement and enjoyment to share with great people, especially our team members who shared the experience together.
Year(s) Of Engagement Activity 2018,2019
URL http://2d-health.com/bluedot-festival-2018/
 
Description European Researchers' Night - Science Uncovered at the Manchester Museum 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The PDRAs involved in this research programme organising a research station on "Graphene and other atomically thin nanomaterials". The focus of this research station is to get chatting to the public and introduce the material that are used daily base in order to achieve the goals of this project.
Year(s) Of Engagement Activity 2017,2019
 
Description Manchester Museum Community Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Our researchers hosted a research station entitled "Good things in Nano Packages". This festival enables members of the public to "go behind the scenes" at the University of Manchester to find out about the work we do and to provide a chance to meet the researchers. This was a fun-filled day of hands-on activities, with live experiments, interactive demonstrations, workshops, music and performances.
Year(s) Of Engagement Activity 2019
URL http://2d-health.com/outreach/manchester-museum-community-festival-2019/