Hybrid Foldamer-Polymer Scaffolds as Novel Biomaterials for Wound Healing Applications

Secondary Supervisor(s): Dr Maria Chiara Arno

University of Registration: University of Birmingham

BBSRC Research Themes: Integrated Understanding of Health (Ageing, Regenerative Biology)

Project Outline

Foldamers are synthetic helical oligomers that adopt stable secondary structures through mimicking the folding patterns of biological systems to generate biomimetic structures of well-defined size and shape.1 In recent years, the biological activity of a diverse array of foldamers as potential antimicrobial and antibacterial agents has excited much interest.1b However, despite the potent antimicrobial properties of foldamers, which make them excellent candidates for topical wound healing treatment, their potential application as wound healing biomaterials has not yet been explored. Moreover, 3D scaffolds obtained from the supramolecular assembly of foldamers often lack the mechanical properties required for their optimal performance as biomedical devices.

Polymers have recently emerged as a promising class of materials for biomedical applications, due to their ease of synthesis and tunable mechanical properties. These attractive features have encouraged their widespread use in a range of applications, including drug delivery, tissue regeneration, and initial studies into their wound healing properties have been reported.2 However, the effective use of polymeric materials for wound healing applications is severely limited by their inefficacy to induce a biological response, which in turn leads to a failure in promoting in situ tissue healing and growth.

In this project, we will address the current limitations associated with the use of individual foldamers and polymers scaffolds as topical wound healing treatments by creating a new class of biomimetic hybrid foldamer-polymer materials which combine and optimize the desirable features of both individual scaffolds. These hybrid scaffolds will form controlled double-network hydrogels in which the mechanical and biocompatibility properties of the scaffold can be orthogonally tuned through modification of either the polymer or foldamer components. Furthermore, the presence of the biomimetic foldamer component allows the scaffold to not only function as a topical wound care device but also to exhibit antimicrobial activity, which has long term implications for increased patient recovery.

During the course of the project, a diverse range of libraries of foldamer-polymer scaffolds will be created in order to permit optimization of the biological performance of these hybrid biomaterials as a new generation of topical wound healing devices with in-built antimicrobial activity. The cytocompatibility and the tissue healing and growth properties of these biomaterials will be assessed in 2D and 3D in vitro cell culture.

Objectives and Methods

i) To create a new generation of biomaterials based on hybrid foldamer-polymer scaffolds and fully characterize them using well-established analytical techniques. Systematically rationally designed libraries of compounds will be generated wherein fundamental structural features (e.g. foldamer and/or polymer length, nature of the foldamer and/or polymer side chains and terminal groups) will be varied to provide a broad scope of substrates for subsequent structure-activity relationship studies.

ii) To determine the mechanical properties of the biomimetic foldamer-polymer scaffolds and establish structure-activity relationships on the influence of key structural features (e.g. oligomer length, terminal group, polymer molecular weight and composition) on their water content, mechanical strength, and cytocompatibility.

iii) To optimize the biological performance of the foldamer-polymer scaffolds as effective wound healing materials with potential antibacterial activity through investigation of the structure-activity relationship, with rationally designed libraries of compounds, to determine the effect of important structural features on their biological activity and their ability to promote tissue healing and growth.

References

1. S. J. Pike et al., Chem. Eur. J., 2014, 20, 15981.

2. M. Mir, Progress in Biomaterials, 2018, 7, 1.

Metallo Foldamer-Proteins Hybrids: Novel Biomimetic Scaffolds for Sensing and Imaging Applications

Secondary Supervisor(s): Dr Anna Peacock

University of Registration: University of Birmingham

BBSRC Research Themes: Understanding the Rules of Life (Structural Biology, Systems Biology)

Project Outline

Foldamers are synthetic helical oligomers that adopt stable secondary structures through mimicking the folding patterns of biological systems to generate structures of well-defined size and shape (Figure 1).1 Foldamers have been the subject of great interest due to their diverse range of applications in supramolecular chemistry. However, despite the importance of biomimetic foldamers and their known ability to mimic the simple natural helical topologies, there are no reports on the development of higher order foldamer scaffolds that can mimic the sophisticated tertiary and quaternary topological structures found in biological systems. Given that the shape of the foldamer scaffold controls their (photo)physical properties and, in turn their function, accessing new to higher order topologies has the exciting potential to open up the field towards optimising existing applications or generating new applications with these novel structures (e.g., as sensors for biological analytes or medical diagnostics).

De novo designed metallopeptide scaffolds that adopt well-defined coiled-coil motifs (Figure 2) can be accessed through combining the fields of inorganic chemistry with synthetic biology (i.e. by incorporating metals into folded biological building blocks (peptides) to create new metallopeptide scaffolds).2 In recent years, de novo metallopeptide coiled-coil scaffolds, have found impressive applications as MRI contrast agents.3 However, the fact that these existing metallopeptide coiled-coil scaffolds are made from biological building blocks, means that they are based on, and therefore limited, to biological shapes and structures. Accordingly, existing systems are restricted to exhibiting a range of shapes and structures, that historically have been limited by evolutionary-imposed constraints, and this severely hinders the optimisation of their performance and the accessibility of new scaffolds for innovative applications.

As it is necessary to tune and improve the photophysical properties of these scaffolds in order to optimise their performance for applications beyond biology, including as sensors and luminescent or magnetic probes for medical purposes, it is vital that we are able to access new topologies that are not restricted to biomimetic systems with evolution-imposed constraints. Accordingly, we will create new hybrid metallofoldamer-protein systems that adopt higher order coiled coil assemblies which are able to adopt a range of novel topologies for generating new applications as potential sensors for biological analytes or effective medical diagnostics tools.

Objectives

1) To create a new class of coiled-coil systems based on hybrid metallofoldamer-protein scaffolds and fully characterize them using standard and advanced analytical and spectroscopic techniques.

2) To generate libraries of hybrid metallofoldamer-peptide scaffolds wherein fundamental structural features (e.g., metal) are systematically varied to provide a broad scope of substrates and a vast library of hybrid scaffolds.

3) To optimise the photophysical or magnetic properties of the new metallofoldamer-protein scaffolds and establish structure-activity and function relationships on the influence of key features (e.g., foldamer length) on their performance as sensors for biological analytes and as luminescent or magnetic probes for medical imaging applications.

Methodology

Each of the objectives of the project require a combination of organic chemistry synthesis and advanced analytical study to generate the hybrid metallofoldamer-protein scaffolds and to assess their stability and performance as sensors and as luminescent or magnetic probes. This work will be carried out under the supervision of Drs. Pike and Peacock in the Department of Chemistry.

References

[1] G. Guichard, I. Huc, Chem. Commun., 2011, 47, 5933.

[2] H. R. Marsden, A. Kros, Angew. Chem. Int. Ed., 2010, 49, 2988.

[3] A. F. A. Peacock et al., Dalton Trans., 2018, 47, 10784.