Peripheral Nerve Regeneration using Electrical Stimulation

Nerve injury is a debilitating condition that often requires surgical intervention to bridge the nerve injury site to promote regeneration of severed axons towards downstream muscles and other organs. Regeneration of neural tissue can potentially be enhanced using biomaterials which maintain similar mechanical properties to that of endogenous tissue whilst also providing topology which directs nerve growth. Research has shown that further enhancements can be achieved through electrical stimulation, and the local delivery of neurotrophic growth factors and small molecules, however the timing, dosage and mechanism of delivery of these needs to be matched to the progression of regeneration so no such treatments are currently available clinically. Another fundamental challenge associated with current nerve repair is the inability to detect the extent to which regeneration is progressing, which is essential to clinical decision making. Currently detection of regeneration progression is crude and relies on the physician physically tapping along the skin, using a method developed over 100 years ago. This project therefore aims to address these challenges through developing novel biomaterials that can sense progression of nerve regeneration and respond to enhance the local regenerative microenvironment through molecular and/or electrical cues.
This approach will be built upon the unique photophysical and electrochemical properties of organic semiconductor-based polymers. The main benefit of using these polymers is to introduce electric stimulation directly to the site of regeneration to improve therapeutic outcomes. The next step would be retaining the electrochemical and photophysical features of the semiconductors developed whilst integrating them into a biocompatible system matching the electrochemical and physical properties of the tissue.
Once a semiconductor-based structure has been successfully synthesized, the material will be encapsulated using self-assembling peptides. This will aid biocompatibility of the semiconductor and provide guidance for the regenerating nerves. Furthermore, peptides can be readily functionalized with imaging modalities, and used in the sustained release of therapeutic compounds. This approach will be explored in order to pioneer a new generation of nerve repair conduits that can sense regeneration and respond by enhancing the local regenerative microenvironment accordingly.
Upon successful design of a biocompatible polymer(s) the materials will be tested using advanced 3D cell culture models that can accurately model the in vivo environment at the site of nerve injury. This approach will be used to assess regeneration, predict host cell responses, and test feasibility of different imaging modalities that could detect the extent of tissue regeneration as well as the effect of electrical stimulation on regeneration.
If the material development and in vitro testing work progresses rapidly and there is sufficient time remaining then next steps will take the technology forward for testing in vivo, although this is likely to form a subsequent project since the development and in vitro testing of the three different functionalities (regeneration support, imaging to detect progression, electrical stimulation) is likely to be a sufficiently ambitious aim for a PhD. This project will therefore pioneer sophisticated new healthcare technology for treating nerve injuries, tailored to the specific patient and injury scenario. The project covers the 2 of the ESPRC remits of Advanced Product Design & Complex Product Characterisation. By attempting to design a therapeutic solution that incorporates the medicinal benefits of peptide constructs and a delivery mechanism of electrical stimulation through organic electronics and, subsequently the extensive characterization work, both of the remits will be covered by the work required during the project.

Pharmaceutical technologies underpin healthcare product development. Medicinal products are becoming increasingly complex, and while the next generation of research scientists in the life- and pharmaceutical sciences will require high competency in at least one scientific discipline, they will also need to be trained differently than the current generation. Future research leaders need to be equipped with the skills required to lead innovation and change, and to work in, and connect concepts across diverse scientific disciplines and environments. This CDT will train PhD scientists in cross-disciplinary areas central to the pharmaceutical, healthcare and life sciences sectors, whilst generating impactful research in these fields. The CDT outputs will benefit the pharmaceutical and healthcare sectors and will underpin EPSRC call priorities in the development of low molecular weight molecules and biologics into high value products.

Benefits of cohort research training: The CDT's most direct beneficiaries will be the graduates themselves. They will develop cross-disciplinary scientific knowledge and expertise, and receive comprehensive soft skills training. This will render them highly employable in R&D in the pharmaceutical, healthcare and wider life-sciences sectors, as is evidenced by the employment record in R&D intensive jobs of graduates from our predecessor CDTs. Our students will graduate into a supportive network of alumni, academic, and industrial scientists, aiding them to advance their professional careers.

Benefits to industry: The pharmaceutical sector is a key part of the UK economy, and for its future success and international competitiveness a skilled workforce is needed. In particular, it urgently needs scientists trained to develop medicines from emerging classes of advanced active molecules, which have formulation requirements that are very different from current drugs. The CDT will make a considerable impact by delivering a highly educated and skilled cohort of PhD graduates. Our industrial partners include big pharma, SMEs, CROs, CMOs, CMDOs and start-up incubators, ensuring that CDT training is informed by, and our students exposed to research drivers in, a wide cross-section of industry. Research projects in the CDT will be designed through a collaborative industry-academia innovation process, bringing direct benefits to the companies involved, and will help to accelerate adoption of new science and approaches in the medicines development. Benefit to industry will also be though potential generation of IP-protected inventions in e.g. formulation materials and/or excipients with specific functionalities, new classes of drug carriers/formulations or new in vitro disease models. Both universities have proven track records in IP generation and exploitation. Given the value added by the pharma industry to the UK economy ('development and manufacture of pharmaceuticals', contributes £15.7bn in GVA to the UK economy, and supports ~312,000 jobs), the economic impacts of high-level PhD training in this area are manifest.

Benefits to society: The CDT's research into the development of new medical products will, in the longer term, deliver potent new therapies for patients globally. In particular, the ability to translate new active molecules into medicines will realise their potential to transform patient treatments for a wide spectrum of diseases including those that are increasing in prevalence in our ageing population, such as cardiovascular (e.g. hypertension), oncology (e.g. blood cancers), and central nervous system (e.g. Alzheimer's) disorders. These new medicines will also have major economic benefits to the UK. The CDT will furthermore proactively undertake public engagement activities, and will also work with patient groups both to expose the public to our work and to foster excitement in those studying science at school and inspire the next generation of research scientists.