Evaluation of Potential of Zwitterionic Salts for the Development of Protein-Resistant Surfaces

Lead Research Organisation: Queen's University Belfast
Department Name: Sch of Chemistry and Chemical Eng

Abstract

Unwanted protein adsorption on medical devices can cause numerous problems such as blood coagulation, inflammation, thrombosis, failure of implants, malfunctioning of biosensors and drug delivery systems, and loss of activity of therapeutically formulated protein solutions. Protein fouling on biotechnological equipment can cause reduced flux through membranes, blocking of separating columns and loss of valuable biomaterials. Since unwanted protein adsorption is a global problem faced by many industries, a lot of efforts have been made to find efficient technology for supressing attachment of proteins on various type of surfaces (metal, polymer, ceramic, silicone). Commonly considered approaches to prevent protein adsorption are based on modification of surfaces of interest by applying coatings formed by self-assembled monolayers (SAMs), grafted polymer layers, and polymer brushes. The coatings support specific functional groups (as zwitterion, hydroxyl) which control surface charge, wettability, hydrophobicity, free energy, and interaction with biomolecules.
The proposed research will evaluate the potential of zwitterionic salt (ZWS)-functionalised coatings and test their potential to suppress protein attachment. ZWSs are a novel class of molecules that combine properties of inorganic salts, ionic liquids and common two-charge zwitterions. ZWSs offer the possibility of functionalization of cation and anion or for use as functional groups attached on long alkyl chains or polymers, and supported on a substrate. They possess four charge centres in their molecules and increased charged surface area leading to strong hydration, as experimentally confirmed. The fact that key underling phenomenon of surface resistance to non-specific protein adsorption is its strong hydration clearly indicates the potential of ZWSs in the proposed application. The project aims to provide understanding at a fundamental level of the interactions between ZWSs, water and proteins through the a range of analytical techniques and scientific methods. These interactions will be reflected in the performances of zwitterionic salt (ZWS)-functionalised coatings, but they will also guide future research strategies and applications.

Planned Impact

A common problem with implantable medical devices is undesirable protein adsorption which can cause inflammation, fibrosis, and infection, thus, causing enormous discomfort to patients and high cost to NHS. The proposal has an explicit long-term goal to develop and commercialise protein-resistant surfaces. Development of coatings that can reduce protein adsorption, if supported by companies (e.g. Abbott UK), would deliver advances to healthcare system and put UK in a leading position in manufacturing in this area. General public and patients would benefit in a great extent, since the advanced medical devices could improve patient's recovery and quality of life.
Since high hydrophilicity is an important requirement in various biotechnological and chemical processes, it is expected that both economic and academic beneficiaries will be extended far beyond the immediate project aims. The potential applications might use ZWSs as additives, main components in mixtures or functional groups supported on substrates.
However, the project will initially be focused on fundamental research which should enhance the understanding of characteristics of zwitterionic salts as functional groups and they effects on both chemistry in solutions and surface chemistry. This is a pioneering work aiming to bring an insight on properties of ZWSs, and their interactions with water and proteins; these findings can be important for many different scientific disciplines and have diverse practical implications.
Working on the project, a PDRA and students (one PhD and two MEng students) will benefit through learning many experimental techniques, developing expertise in project management, improving communication skills and experience in outreach activities, and engagement with media and public. These acquired skills will improve their employability in both academia and industry as highly qualified workers.
The project would help MB to consolidate a successful research group and extend her network of collaborators. It is expected that collaborative work and joint expertise will enhance knowledge transfer between institutions on both national and international level, and result in high quality publications. It will help MB to support her applications for future funding.

Publications

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Hammond OS (2020) Hydration of sulfobetaine dizwitterions as a function of alkyl spacer length. in Physical chemistry chemical physics : PCCP

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Level G (2020) Multicharge zwitterionic molecules: Hydration, kosmotropicity and anti-fouling potential. in Journal of colloid and interface science

 
Description It was recently found that two-charge zwitterionic moieties such as sulfobetaines and carboxybetaines provide high resistance towards protein adsorption and they have been recognized as promising alternatives to polyethylene glycol-based coatings which are currently a benchmark for antifouling surfaces.
The main objective of the project was to investigate and compare the anti-fouling potential of two-charge zwitterions and two novel classes of multi-charge zwitterionic materials (MCZWs.) Furthermore, the project was supposed to provide direction towards the development of efficient protein-resistant coatings that could outperform currently available solutions in biomedical and engineering applications.
The project objectives were met and the main findings were published. The project carried out the design, synthesis, and selection of the most promising MCZWs that possess the highest hydration capacity and kosmotropicity, which are scientifically proved the main requirements for creating a protein-resistant surface. The current experimental findings suggest that these innovative MCZW materials possess superior hydrophilicity, kosmotropicity, and anti-fouling potential over simple two-charge molecules, highlighting these structures as ideal to be tested and employed as functional groups in the design of advanced hydrophilic and protein-resistant surfaces. The study has demonstrated that these materials have the potential to become the next generation of coatings to inhibit non - specific protein binding
Exploitation Route Since a positive outcome was achieved and the project identified successful candidates to be used as functional groups attached to polymers a further challenge would be a practical implementation of the developed material. The research should be extended through collaboration with experts in surface grafted polymer brushes functionalized with MCZWs since they provide the most common and efficient way of surface modification of materials of interest in the proposed context.
Sectors Healthcare

Manufacturing

including Industrial Biotechology

Pharmaceuticals and Medical Biotechnology

URL https://www.sciencedirect.com/science/article/abs/pii/S0021979719314687?via%3Dihub
 
Description The project enabled the employment of a PDRA, an early-stage career researcher, providing valuable opportunities for him to engage in extensive scientific training in a new subject. Additionally, the PDRA acquired skills in scientific writing, project management, and the preparation of diverse fellowship applications. These acquired skills not only contributed to the advancement of the project but also supported the PDRA's further progression in his academic career. A part-time technician also benefited significantly from the project by receiving extensive training in various analytical and experimental techniques, as well as co-authorship of several scientific publications. This training proved instrumental in helping the technician secure a permanent position within an academic environment. The technician's newfound expertise has translated into robust scientific support of research within her new workplace. During the project's duration, the Principal Investigator (PI) gained valuable experience in project management while solidifying her position in the specialized field of materials and coatings for healthcare technology. Additionally, the project facilitated the establishment of collaborations with other research groups, thus promoting knowledge exchange. Importantly, knowledge sharing has been instrumental in growing the PI's ambitions from the initial project objectives to more advanced material and product design. It is anticipated that the newly generated idea, the multidisciplinary approach achieved in collaboration with the co-workers in the School of Pharmacy, and the outcomes generated will attract attention from industrial partners and create additional funding avenues. However, a valuable lesson learned from the project is that expecting product development and commercialization and direct significant long-term societal benefits from a relatively modest budget project (109k) may have been overly ambitious.
First Year Of Impact 2022
Sector Education,Pharmaceuticals and Medical Biotechnology
Impact Types Societal

Economic

 
Title Association and liquid structure of zwitterionic salts-water mixtures 
Description -fouling surfaces are a critical requirement for a wide range of biomedical applications, such as medical implants and biosensors. Poly(ethylene glycol) is widely used despite some serious drawbacks such as susceptibility to oxidation. Zwitterionic polymers have been recognised as promising alternatives with higher chemical stability, effectiveness to resist biofouling, and better long-term performance. The higher resistance of polymeric zwitterionic materials has been explained in terms of the greater electrostatic hydration of charged zwitterionic terminal groups compared to PEG. New zwitterionic salts (ZWSs) that consist of a cation and an anion, with an additional zwitterionic moiety embedded in either the cation or the anion, have even greater larger hydration shells and stronger interactions with water and may leading to enhanced anti-fouling characteristics. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact The solvation and structure of multicharged zwitterions moieties in concentrated aqueous solution were determined using neutron diffraction with isotopic substitution (NDIS) combined with modelling of the measured structure factors using Empirical Potential Structure Refinement (EPSR). Strongly directional local hydration was observed in the polar regimes of the zwitterions with 48-52 water molecules. Overall, the multicharged zwitterions were highly hydrated, providing experimental evidence in support of the potential formation of protein-resistant hydration layers at zwitterion-water interfaces. 
URL https://data.isis.stfc.ac.uk/doi/INVESTIGATION/87768598/
 
Description The Centre for Advanced Technologies for Healthcare (Biofilm) Network 
Organisation Queen's University Belfast
Department School of Pharmacy
Country United Kingdom 
Sector Academic/University 
PI Contribution PI engaged with the Biofilm focused group and established an multidisciplinary collaboration with researchers from School of Pharmacy (QUB). Pi contributed with a detailed project plan and written research proposal on an innovative approach for developing strategies to combat biofilm formation.
Collaborator Contribution The partners contributed by sharing complementary scientific expertise, equipment, and access to industrial engagement opportunities.
Impact This collaboration is still in its relatively early stages, with two key outcomes expected to be achieved within the next 2-3 months. These outcomes include the submission of a scientific publication and a project proposal to be presented to the funding body.
Start Year 2024
 
Description The Centre for Advanced Technologies for Healthcare (Biofilm) Network 
Organisation Queen's University Belfast
Department School of Pharmacy
Country United Kingdom 
Sector Academic/University 
PI Contribution PI engaged with the Biofilm focused group and established an multidisciplinary collaboration with researchers from School of Pharmacy (QUB). Pi contributed with a detailed project plan and written research proposal on an innovative approach for developing strategies to combat biofilm formation.
Collaborator Contribution The partners contributed by sharing complementary scientific expertise, equipment, and access to industrial engagement opportunities.
Impact This collaboration is still in its relatively early stages, with two key outcomes expected to be achieved within the next 2-3 months. These outcomes include the submission of a scientific publication and a project proposal to be presented to the funding body.
Start Year 2024
 
Title Multicharge Zwitterionic Materials 
Description The current experimental findings suggest that the novel multicharge zwitterionic materials developed through this project possess superior hydrophilicity and kosmotropicity over simple two-charge molecules currently used, highlighting these structures as ideal to be tested and employed as functional groups in the design of advanced hydrophilic and anti - fouling surfaces. 
Type Of Technology New Material/Compound 
Year Produced 2020 
Impact The project demonstrated that the developed multicharge zwitterionic materials have the potential to become the next generation of coatings to inhibit non - specific protein binding. 
URL https://www.sciencedirect.com/science/article/pii/S0021979719314687?via%3Dihub
 
Description industrial consortium 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact MB and GL as members of the QUILL Research Centre at QUB presented the project results to an international industrial consortium in March and October 2019. Potential support from interested industrial sponsors for taking the project to the next stage is currently under discussion.
Year(s) Of Engagement Activity 2019