Please Note: The main page lists projects via BBSRC Research Theme(s) quoted and then relevant Topic(s).
Incorporating mechanical bonds into peptides
Secondary Supervisor(s): Professor Sébastien Perrier, Dr Stephen Fielden
University of Registration: University of Warwick
BBSRC Research Themes:
Project Outline
Background:
The mechanical bond is found in interlocked molecules, such as rotaxanes and catenanes. It provides a linkage between molecular components that combines the robustness of the covalent bond with dynamics of supramolecular interactions. Mechanical bonds have broad applications in fields such as sensing, catalysis and artificial molecular machines, but perhaps the most promising venue for these units is in mechanically interlocked materials.[1] When mechanical bonds are incorporated into polymers, it often results in drastically improved material properties and new features like stimuli-responsiveness and self-healing.
Surprisingly, the use of mechanically interlocked materials for biological materials applications is highly underdeveloped, despite the constant need for disruptive technology and innovative approaches in the biomedical sciences.[2] The reason for this is mainly the synthetic difficulty in obtaining biocompatible interlocked systems, which limits the range of accessible polymeric interlocked architectures. Developing new chemistry to access interlocked materials is hence extremely important for realising the full potential of the mechanical bond in biology.
Objectives:
In this joint project between the Universities of Warwick and Birmingham, we will use state-of-the-art methods for mechanical bond synthesis to access new types of interlocked biomaterials.[3] We want to take polymers normally used as biomaterials in drug delivery, tissue engineering and regenerative medicine and show that we can put macrocycles around the polymer backbone with precision. This will then allow us to rationally modify physical properties such as solubility, improve mechanical performance and add functionality such as stimuli-responsiveness, adaptability and self-healing. The key to this is to use kinetic control for both the polymer and mechanical bond formation, to create materials known as polyrotaxanes. The PhD project will (1) explore multiple synthetic approaches to create novel mechanically interlocked biomaterials using active template synthesis, (2) study the self-assembly properties of synthesised biomaterials and (3) demonstrate their application in fields such as drug delivery and tissue engineering. Both linear mechanically interlocked polymers and larger cross-linked interlocked networks (slide-ring materials) will targeted using this approach. Specifically, a large focus will be on synthesis and characterisation of the obtained biomaterials, but the student will also work on drug release studies (using model cancer drugs), self-assembly studies and basic studies aimed towards tissue engineering applications (cell adhesion, proliferation/migration studies etc). We are particularly interested in studying the behaviour of our materials with stem cells, as polyrotaxanes are known to modulate mechanotransduction and hence stem cell differentiation in exceptional fashion.[2] Successful completion of the PhD project will generate an entirely new class of interlocked biomaterials with high potential for translational healthcare applications.
Methods:
The project is truly interdisciplinary and will involve a combination of supramolecular chemistry, synthetic organic chemistry, polymer chemistry, drug delivery and cell biology. The project is particularly well-suited for students with a strong interest in supramolecular chemistry and biomaterials, but a range of different background and research would also be welcomed. This work will be carried out at both the Universities of Warwick and Birmingham under the joint supervision of Dr Fredrik Schaufelberger (Warwick – biomaterials/supramolecular) and Dr Stephen Fielden (Birmingham, polymers/supramolecular/microscopy).
References
[1] a) Mena-Hernando and Pérez, Chem. Soc. Rev. 2019, 48, 5016-5032; b) Rowan et al. Nat. Rev. Mat.2021, 6, 508-530.
[2] Schaufelberger et al. Chem, 2023, 9, 1378-1412.
[3] Fielden, ChemSystemsChem, 2024, 6, e202300048
Techniques
The project is highly multidisciplinary and the student will receive extensive in-depth training from both participating research groups. In particular, training in advanced multistep organic synthesis (reaction set-up, workup, purification with column chromatography/crystallisation etc), supramolecular chemistry (binding studies, analysis of intermolecular interactions) and polymer chemistry (macromolecular characterisation via GPC, mechanical properties investigation, self-assembly) will be given, along with instrument training for a range of analytical techniques such as NMR spectroscopy, mass spectrometry, gel permeation chromatography, IR spectroscopy, DSC, AFM, TEM, SEM, and basic cell biology facilities (cell culture, confocal fluorescence microscope, plate reader assays etc).
