Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - Multi-SIP Hydrogel (A multifunctional self-immolative hydrogel for accelerating the healing of chronic wounds)

Teaser

Approximately 1–2% of people in developed countries—particularly the elderly and sufferers of diabetes or obesity—will experience in their lifetime a chronic skin wound characterised by tissue loss without spontaneous healing. This represents a major public health...

Summary

Approximately 1–2% of people in developed countries—particularly the elderly and sufferers of diabetes or obesity—will experience in their lifetime a chronic skin wound characterised by tissue loss without spontaneous healing. This represents a major public health concern and a burden of several billions of dollars to not only the European, but also the global economy. Unfortunately, this burden is likely to grow as the world’s population ages and as diabetes and obesity become increasingly prevalent. Considering the growing need for more effective wound treatment options, the objective of this MSCA Fellowship has been to develop a dynamic hydrogel system containing stimuli-degradable self-immolative polymers (SIPs) to act as ‘sense-and-deliver’ modules for releasing drugs into chronic wound environments. SIPs are ideally suited to this application because they undergo complete depolymerisation in response to biochemical cues, making them useful stimuli-responsive materials. This project has made significant progress toward a multi-responsive hydrogel for accelerating chronic wound healing. I have developed a modular platform for preparing synthetic block copolymers featuring self-immolative side-chains. In water, these polymers self-assemble into nanoparticles (‘SIPsomes’), which can be loaded with drugs for treating chronic skin wounds. Importantly, these SIPsomes can be degraded by biochemical signals present within the wound environment, thereby triggering the release of specific drugs at different stages of the wound healing process. As proof-of-concept, successful payload delivery in vitro from a peroxide-responsive SIPsome has been demonstrated. This SIPsome will be used to interrupt the chronic inflammatory cycle of chronic wounds by delivering an inhibitory drug in response to reactive oxygen species. Ongoing work seeks to expand the suite of SIPsomes to target other stages of wound healing (proliferation, remodelling) toward a multifunctional SIPsome hydrogel that dynamically addresses several wound healing stages.
This highly ambitious project involved collaborations between the Karolinska Institute and Imperial College London to synthesise and study this complex new biomaterial. The cross-disciplinary expertise from these collaborations, and my placement within the world-renowned Stevens Group, facilitated the promising outcomes of this project. Ongoing international collaborations established during this project will further develop this system for future clinical applications.

Work performed

This Fellowship has achieved the following results so far:
1. Monomer components for preparing RAFT polymers and SIPsomes were synthesised and characterised. Monomer synthesis was optimised in several stages to overcome challenges encountered with the first-generation monomers. A modular isocyanate-based strategy was devised for preparing monomers that can be polymerised by RAFT. This strategy will be the basis for preparing other stimuli-responsive SIPsome precursors in ongoing work.
2. Block copolymers carrying self-immolative groups were prepared by RAFT polymerisation using novel monomers synthesised in this project. Polymers were characterised and their self-assembly studied by light scattering and electron microscopy. As proof-of-concept, peroxide-degradable SIPsomes were prepared and successful payload release demonstrated. Based on this promising data, SIPsomes that respond to other wound healing stimuli (e.g., metalloproteinases) are being prepared.
3. A covalently-crosslinked alginate hydrogel was developed using the tetrazine-norbornene ‘click’ reaction, which permits crosslinking of the gel and functionalisation with cell-adhesive peptides. First-generation hydrogels were characterised by rheometry in collaboration with Imperial College London. These data are being used to optimise the hydrogel stiffness to match human skin. Upon finalisation of the SIPsome design, the alginate hydrogel will serve as a scaffold to encapsulate the SIPsomes and support cell growth in upcoming biological studies following the completion of this MSCA fellowship.
4. This project established a novel use for a commercial catalyst to polymerise poly(benzyl urethane) SIPs at much lower temperatures than previously reported (50 °C compared with 110 °C). Lowering the polymerisation temperature expands the scope of these materials by permitting the synthesis of SIPs carrying temperature-sensitive functional groups. Moreover, avoiding toxic tin-based catalysts typically used for this reaction will improve biocompatibility and biological safety.
5. Significant progress was made towards a new ‘click’-based strategy for post-polymerisation capping of SIPs using the copper(I)-catalysed azide-alkyne cycloaddition reaction. This method has high potential for significant impacts within polymer science since the post-capping reaction is not sensitive to water or oxygen, is modular and can solve issues with sterically-hindered capping alcohols.

The key findings from this project have been disseminated at the IUPAC World Polymer Congress (July 2018) and at several invited seminars in Australia and the UK. The Marie Skłodowska-Curie Actions Fellowship and the European Commission have been acknowledged for funding under the Horizon 2020 Programme. During the funding period, I also engaged in public outreach (including Stockholm’s largest public science event, ‘ForskarFredag’) to communicate my research to broader audiences. I also contributed to undergraduate teaching and research student training to foster transfer of knowledge to younger scientists. Two high-quality publications are in preparation, which will report the final results from this project. These publications will acknowledge all European Commission funding and will comply with EU open access policies.

Final results

The results from this Marie Skłodowska Curie project have advanced the state-of-the-art in several areas of polymer/materials science. Firstly, the RAFT-based SIPsome platform uses an innovative self-assembly approach as a straightforward way to encapsulate and deliver drugs in response to biochemical stimuli. RAFT polymerisation makes this approach inherently modular as additional functional groups may be introduced by copolymerisation or block extension. Secondly, this project demonstrated a new use for a commercial catalyst to polymerise SIPs at low temperatures while avoiding tin-based catalysts. Thirdly, a novel ‘click’-based strategy for post-capping SIPs has been developed, which may help to overcome limitations of existing methodologies. This project has thus established new methods for preparing stimuli-responsive soft materials, which, it is hoped, will advance new discoveries in polymer chemistry and biomaterials engineering.

Website & more info

More info: https://bit.ly/2JngaDF.