Engineering Responsive Nanomaterials for Pulsatile Neural Regeneration

Lead Research Organisation: University College London
Department Name: Institute of Neurology


Triggerable drug delivery from polymeric implants offers the possibility of generating remote-controlled drug release profiles that may overcome the deficiencies of conventional administration routes such as intravenous injections and oral administration. We propose here the development and biological characterisations of an injectable electro-responsive hydrogel hybrid scaffold capable of releasing therapeutic agents in response to an externally applied electrical field. This type of delivery system will ideally actuate the timing, duration, dosage, and location of drug delivery and in the meanwhile enable remote, repeatable, and reliable switching of therapeutic agent release. Numerous types of disorders including neurodegenerative disorders could benefit from this 'smart' material. Our interest is on the treatment of Parkinson disease, which stands among the common progressive neurodegenerative disorders; it has been demonstrated that a selective loss of pigmented dopaminergic neurons in the substantia nigra (SN) was the main cause of this disorder. Developing a remote-controlled delivery system capable of releasing a nerve growth factor in this specific area of the brain that could regenerate dopaminergic neurons would provide a novel and powerful tool for the therapy of Parkinson's disease. This proposal aims to translate our innovative delivery system as a potential therapy for Parkinson's disease; this system, based on an injectable thermo-responsive gel hybrid scaffold, will deliver in a pulsatile fashion, a nerve growth factor, retinoic acid (RA) upon the on/off application of an external stimulus in the SN. The differenciation of neural primary cells into dopaminergic neurons by chronic stimulation via Retinoic acid (RA) has been investigated in vitro as potential therapeutic solution. Therefore, the in vitro and in vivo capability of these materials will need to be assessed.

Planned Impact

This project will have an impact in academia and industry and will address all those interested in targeted brain delivery, bionanoengineering and nanomedicine. This project will encourage the transfer of knowledge, methods and ideas across disciplines, expand the capacity of engineered medical devices for the treatment of neurodegenerative disorders, and provide additional knowledge on the intricate processes and mechanisms involved in differentiation of primary cells. Currently, the nanomedicine laboratory at the UCL School of Pharmacy is among the European leader in the field of nanomedicine; The Functional Neurosurgery Unit at the Institute of Neurology is a highly specialised multi-disciplined team (the Deep Brain Stimulation team) which includes three of the world's leading experts dedicated to the use and research of Deep Brain Stimulation for the neurosurgical treatment of movement disorders. This fellowship will contribute to the reinforcement of an existing collaboration between the Nanomedicine Laboratory at the UCL School of Pharmacy and the Functional Neurosurgery Unit at the UCL Institute of Neurology and will establish their position further in their respective field. This collaboration is expected to push this innovative research to a more applied level with the collaboration of clinical experts. The proposed project that mixed different skills of the fellow's background is also expected to enlarge and reinforce her field of scientific expertise. These two laboratories (Nanomedicine laboratory and Deep Brain Stimulation team at the Institute of Neurology) have previously collaborated: Dr T. Nakajima, a visiting neurosurgeon from Japan working with UCL Institute of Neurology (IoN) joined the Nanomedicine laboratory where he established a rat model for Parkinson's disease and developed behavioural tests. This collaboration led to the successful transfer of knowledge in particular in surgical procedures that were required for the project and an article in a high impact journal in Neuromedicine is currently in preparation. The capacity to build a long-lasting collaboration between a pharmaceutics laboratory and a biomedical and tissue engineering laboratory performing clinical studies is a realistic expectation and will contribute to the development of ground breaking research in the field of nanomedicine and neuroscience. It is expected that additional national, EU or independently funded collaborative project will follow the developments achieved by this project. Such a collaborative project promises to bring about a long term benefit for the development of UK and European science and its clinical translation.
The proposed research is relevant for pharmaceutical and medical companies interested in developing novel therapeutic approaches to the brain. This project is intended to pioneer a novel approach in the field of drug and delivery that will be translated clinically as a novel medical device with higher therapeutic capabilities to reduce the suffering of patients with neurodegenerative disorders. The proposed research is driven by the expected clinical application that will lead to a push of applied multidisciplinary cross-faculty and cross-country research at universities and institutes. Future funding for clinical testing and commercialization of these novel artificial spermatozoa based delivery systems will be sought from prospective industrial partners.The United Kingdom (UK) has a good starting position in the nanomedicine area and represents one of the largest medical device markets in the world. This project is expected to add value for the United Kingdom. It will improve the healthcare for British and European citizens and provide better therapy options for patients suffering of neurodegenerative disorders. Stimulating this type of research in academia and in industry can only be beneficial for UK manufacturing and development.


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Description This project aims to develop an injectable electro-responsive hybrid polymeric implant for the pulsatile and targeted delivery in the brain of Retinoic acid (RA), a growth factor that plays a crucial role in neuron patterning, differentiation and survival in the brain. This system was an initial prototype that resulted from the EPSRC Grand Challenge project of this previously unreported electro-responsive delivery system. Therefore, the main objective of this project was to translate engineered 'smart' materials such as a hydrogel hybrid scaffold that can respond to an external electric field into a potential treatment for neurodegenerative disorders including Parkinson disease. The polymeric implant is composed of a) multi-walled carbon nanotubes (MWNTs) as a conductive additive and b) electro-responsive RA-loaded microgels, both encapsulated in a thermoresponsive gel matrix such as Pluronic F127 that is designed to be an injectable solution at room temperature and that can form a solid gel matrix at body temperature. The release of RA is expected to initiate and enhance the differentiation of neural primary cells into dopaminergic neurons in the Substantia Nigra (SN). The scaffold was successfully developed and the preparation parameters such as RA loading into the PMAA nanoparticles, and carbon nanotube and Pluronic F127 concentration were optimised for the in vitro RA release of therapeutically relevant doses from the scaffold at 37°C. The constant release of high amounts of RA was achieved in vitro in HEPES buffer at pH 7.4 upon the application of the electric field for a period of 10 min. This device can now be tested for biocompatibility and for the in vitro assessment of RA release efficacy with a specific model, i.e. primary cell differentiation into dopaminergetic neurons and the in vivo assessment of RA delivery efficacy in a rat Parkinson's Disease (PD) model.
Exploitation Route Using the results of this study would contribute to the development of more efficient tools of therapeutic/imaging capability and will have a great impact on treatment options for neurodegenerative disorders. Moreover, development of effective injectable nanomedicines, in addition of controlling the in vivo targeting will be a ground-breaking technology for clinical use. Inventions of more effective therapeutics with minimal side effects will have a huge impact on the comfort and quality of life of neurological patients and their families. Benefits will extend to various healthcare professionals (neurologists, neurosurgeons, nurses, and pharmacists). The main objective in this project has been the development of a model of electro-responsive drug delivery system for the remote - controlled delivery of retinoic acid (RA), a nerve growth factor, for the regeneration of lost neurons in neuro-degenerative disorders. For the clinical translation of this device, this sophisticated scaffold will be combined with the DBS technology to achieve the pulsatile release of RA in a particular area of the brain where there is a loss of dopaminergic neurons as a consequence of PD. The possible exploitation routes, in a second stage of a proof-of-principle neurological application, would be to develop a second version using biodegradable polymeric matrix including poly(lactic acid) or poly(L,D glycolide). In addition, if this second version of the system demonstrates good results in vivo in a rodent PD model, it will allow re-engineering for biodegradability that could lead to the generation of a new type of medical device. We consider this as a small but critical step towards the further development of a new type of advanced drug delivery system and medical device that was originally developed during the Grand Challenge project.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology