A Portable Electrohydrodynamic Device for in-situ Production of Multi-Layered Drug-Loaded Meshes

Lead Research Organisation: University College London
Department Name: School of Pharmacy

Abstract

The proposed research describes a novel engineering approach to point-of-need delivery of controlled release medications for wound and burn treatment, based on an innovative portable device which allows in situ generation of nano-/micro fibrous meshes. These fibres can contain multiple layers of active pharmaceutical ingredients (APIs) in a core-shell configuration (potentially up to at least four layers), allowing compartmentalisation of agents ranging from proteins to low molecular weight antibiotics and including innovative therapeutic oligosaccharides.

Nano- and microfibres with compartmentalised structures are currently attracting a great deal of interest within the drug delivery arena due to the advantages of high surface area, high fluid permeation, ready separation of incompatible drugs into physically distinct environments, the ability to tune drug release rates via incorporation into controlled release polymers and the physical flexibility and versatility of the macroscopic mesh structure. Furthermore, given recent emphasis on combination therapies, the possibility of generating compartmentalised systems using, for example, coaxial and multi-axial electrohydrodynamic (EHD) technology is highly attractive. One example of such an application is the treatment of wounds and burns, whereby the flexibility of shape of the meshes to neatly fill the lesion, the high fluid permeation of the mesh facilitating tissue regrowth, the tunable release of therapeutic agents and the biodegradation of the mesh are all perfectly feasible attributes that would render a drug-loaded nanofibre approach highly advantageous.

A further possibility, not yet realised in practice, is the generation of micro/nanofibres in situ at the point of trauma. Were this to be possible, then valuable time to treatment would be saved as agents designed to stop bleeding, prevent infection, reduce pain or promote healing could be administered quickly in a form which could be applied to a wide range of lesion architectures and areas. Indeed, a portable system could also be used in conflict situations, for patients with mobility difficulties being treated at home for conditions such as diabetic ulcer or for otherwise medically inaccessible regions such as refugee camps, while the use of biodegradable polymer bases would allow the mesh to simply be resorbed over a period of time without damage to the lesion associated with dressing removal. Moreover, the capability to generate highly permeable microfibrous meshes at point-of-need enables an alternative nasal route for sustained and controlled drug release when oral/intravenous drug delivery is rendered impractical during emergencies where the patient may be unconscious with poor vein access (e.g. heroin overdose) or may even be having a seizure (e.g. status epilepticus).

Overall, therefore, a 'field' system for simple and inexpensive administration of complex drug-loaded fibre meshes would have huge patient benefit for a wide range of conditions and would represent a significant breakthrough in engineering-led therapeutic development. Clearly, however, such a system would present a series of profound engineering challenges. Despite recent advances in fibre production technology, the generation of fibres with compartmentalised systems requires bulky, expensive (>£20k), bench-top high voltage supply and syringe pumps that are confined to a laboratory or factory environment. Developing a portable, hand-held, cheaper (<£2k), miniature EHD device that can generate multilayered therapeutic materials could revolutionise the practical applicability of micro/nanofibres. We believe, based on our work to date, that such an approach is now possible and the project outlined here, which focuses on the engineering issues associated with the development of our prototype device and the challenges of drug incorporation, would lay the foundation for the use of this approach in a wide range of therapeutic applications.

Planned Impact

The proposed development of a new engineering-based therapeutic approach, developed by a cross-disciplinary team of pharmaceutical scientists and engineers, will have beneficial impact on the patient population as well as communities within academia and industry. The development of point-of-need delivery of complex medications, particularly for emergency situations, has clear implications for patient wellbeing. Specifically, a successful outcome to the project will entail not only a new means of generating micro- and nano-fibres in situ but will also develop drug-loaded systems for a defined therapeutic application. While wound and burn treatment are an obvious application for the device and represents the focus here, other applications include emergency treatment for overdose or epilepsy via nasal administration (e.g. nasally administered naloxone), usage during surgery or application for the treatment of fistulae. In addition, any reduction in hospital residence time or surgical procedure requirements caused by more immediate and effective treatment will render the economic argument for the development of this approach extremely compelling. Consequently we would argue that the device would have a potentially significant impact on healthcare in the UK. We would also highlight the reputational and international benefits of the project; the UK has a long-standing tradition of assisting patients in countries that lack the healthcare infrastructure of the UK and this device could represent a significant tool in treating a wide range of diseases (e.g. traucoma, leishmaniasis, both of which can potentially be treated using fibre-based approaches; it could also conceivably be used for mass oral immunisation).

In addition to the impact of in situ delivery, the development of drug-loaded systems has potential impact for the pharmaceutical and biotech industry as well as the industry associated with the supply of materials relevant to the field, as evidenced here by the support from industrial collaborators. The use of fibres for drug delivery (in addition to the existing and recognised use as scaffold materials) is very much an emerging field and this project will be at the cutting edge of this new approach, particularly given the possibility of forming multi-layered systems which in turn allows both compartmentalisation and tailored release profiles. The potential for commercial exploitation of the device and approach for specific treatments is very considerable and indeed, we would also see partnership with the pharmaceutical industry for specific treatment development as being a real possibility in the future, with associated benefits for this sector. Furthermore, the in-field ability to form micro/nanofibres of defined and complex architecture has clear therapeutic and biomedical applications beyond those outlined here and indeed beyond the healthcare sector; the device could also be extremely useful in the textile, electrical and building industries, for example.

There will also be academic impact on both the pharmaceutical and engineering communities, both separately and as an example of successful collaboration between pharmaceutical scientists and engineers. As outlined above, the use of fibres as delivery systems is an emerging field whereby the current consortium is a major contributor, while the manufacture of multifunctional/multi-component micro- and nano-fibres is a highly topical area within the engineering community. The suggested outcomes would serve both communities in a positive manner.

Publications

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Description A Portable Electrohydrodynamic Device for in-situ Production of Multi-Layered Drug-Loaded Meshes

1. Design of first version of portable electrohydrodynamic device completed. Device have been used to produce various drug-loaded fibre types. An upgrade of this device (Mark 2, more portable but highly versatile and functional is ongoing)

2. First paper on this project ACCEPTED FOR PUBLICATION in Macromolecular Materials & Engineering. Title: An Inexpensive, Portable Device for Point-of-Need Generation of Silver-Nanoparticle Doped Cellulose Acetate Nanofibers for Advanced Wound Dressing

3. Mark 2 four-motor driver design for user interface (to be installed into custom motherboard): We have given the green light to Trinamics (German headquarter, USA branch). This will be designed and manufactured over the next three months.

4. Mark 2 motherboard for user interface: UK-based RMCybernetics Ltd (Richard Morrow) is working with me to design the motherboard, which incorporates the motor drivers (item 2 above) onto motherboard along with designing HV control, pump control, digital screen interface. Expecting the user control for Mark 2 to be assembled by June 2018.

5. Mark 2 HV unit upgrade: in consultations with XP Power for designs

6. Mark 2 overall inner and outer assembly, 3D printing of casing and packaging: Expecting final Mark 2 device ready around end of September 2018.

7. First draft of second paper completed
This reviews a multi-layered fibre produced by our portable electrospinning device
Structure of fibre produced is as follows:
Innermost core; Metronidazole in PCL for extended release
Middle layer; Iodine in PVP acting as antiseptic for sanitising wound
Outermost layer; PEG as fibre for wound dressing

Fibre characterisation by
XRD and FTIR to confirm molecular composition
TEM showing multi-layered fibre
SEM showing fibre morphology and size distribution

Performance
Release study
Comparison with other formulations (Metronidazole cream and metronidazole/Iodine cream; prepared to be similar in drug content to fibres) to determine the value of fibre-based wound dressing

Mathematical modelling to predict the value of drug release from a multi-layered fibre system

Antibacterial activity
Antibacterial activity of fibres compared with those of creams formulated to contain equivalent amount of drug as in fibres

8. Comparison with conventional benchtop electrospinning (potentially for 3rd publication)
Delivering metformin in gelatine fibres, single needle. Fibre samples generated (awaiting SEM and further characterisation)
Gelatine promotes wound healing. Metformin has recently been confirmed to be useful for managing diabetic ulcers. Gelatine fibres are extremely water soluble, but proposing UV crosslinking to different extents and measuring the effect of crosslinking and other variables on release of metformin from these fibres.

9. Ongoing discussion on possibility of testing the performance of fibre output from this portable device on whole live animals
Exploitation Route We are hoping to protect the most up to date prototype of the device. We are also looking to put a masters student on the Mark 1 device as part of their degree programme, plus we intend to produce a stream of open access publications that will enable others to engage with our work. We have also formed links with UCL Division of Surgery who will work with us to develop the clinical aspects of the project.
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description Supply of materials 
Organisation BASF
Country Germany 
Sector Private 
PI Contribution BASF are named partners on the grant - we have a long standing good relationship with them.
Collaborator Contribution They have sent us polymers that we will be using to develop the nanofiber gun.
Impact The gift of the polymers has allowed us to extend the range of materials that we can explore for use as matrices for the nanofiber gun
Start Year 2013
 
Description Meeting with industrial partners 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Industry/Business
Results and Impact Meeting with industrial partners to demonstrate successful development of fiber gun and discuss future direction of the project
Year(s) Of Engagement Activity 2018