Exploitation of Pressurised Gyration as an Innovative Manufacturing Route for Nanofibrous Structures

Lead Research Organisation: University College London
Department Name: Mechanical Engineering

Abstract

There has been considerable interest in developing nanofibrous systems, composed of meshes of ultra-thin fibres, for usage in several key industrial applications, for example in pharmacy. In brief, such systems allow very favourable physical characteristics such as a high surface area to volume ratio which in turn allows rapid drug release. However, a major obstacle to such approaches is the possibility of producing such systems at a realistic scale. For example, well established techniques such as electrospinning can only generally produce gram quantities of material in an hour. Our proposal is that by using a pressure gyration technique developed at UCL we will be able to rapidly produce drug or active-loaded nanofibres in kilogram quantities, thereby rendering the use of such materials commercially feasible. The method basically consists of a cylinder with a bank of holes around its middle axis. By applying gas under pressure and rotating the system rapidly, it is possible to extrude a solution of the polymer from the holes under ambient temperatures, with the solvent being driven off to produce nanofibres on a surrounding collecting plate. We will expand further the capabilities of the pressurised gyration process by building a more upmarket and powerful manufacturing device. We will also study the physics of the process in greater detail in order to be able to process control and predict the output characteristics of the products. We have already demonstrated that the technique can produce such quantities of unloaded material, hence it is entirely reasonable to suggest that the approach can be used for pharmaceutically relevant systems. We plan to demonstrate and explore the utility of the approach using three important and well-defined application areas. Firstly, we will study polymeric fibres loaded with fine particulates so that we can develop capability to use pressurised gyration to manufacture bioactive scaffolds, graphene precursors (via graphene oxide-loaded polymeric meshes), antibacterial fibrous bandages/masks etc. Secondly, we will look at the formulation of poorly water-soluble drugs for oral administration. This is a major problem for the pharmaceutical industry, as a drug must dissolve before it is absorbed through the gastrointestinal tract. It is known that dispersing such drugs in polymers may enhance that dissolution rate; we argue that the nanofibres will be even more effective due to the porous nature of the mesh and the very high surface area of such a system. Thirdly, we suggest that this method may be used as an alternative to freeze drying, whereby proteins are prepared in a solid form that may be easily reconstituted prior to injection on addition of aqueous solvent, a process that is expensive and physically and chemically traumatic for the protein. Hence if we are able to show that the pressure gyration technique also produces a stable, solid and easily reconstituted physical form then the implications for pharmaceutical production of injections would be considerable. By exploring these three application we will not only develop pre-competitive knowledge regarding the systems in question but we would also be introducing the pressure gyration technique into the industrial arena. In particular, we will be working with Astra Zeneca who have considerable expertise and interest in developing non-conventional pharmaceutical dosage forms to suit the requirements of their drug products; the company will work closely with the academic partners to advise on applicability and scale-up potential.

Planned Impact

The project aims to develop a new method of nanofibre manufacture. The impact of this will be in two broad areas, relating to the development of the process for pharmaceutical use and to three specific areas of study that we propose here. In terms of the process itself, that of pressure gyration (PG), we will have explored and validated a method which allows nanofibre formation under much less invasive conditions than is currently the case and at a comparatively low cost, while also allowing large scale manufacture to be performed. These are crucial considerations as, at present, methods such as electrospinning are attracting considerable interest but uncertainties regarding, for example, the effect of the high voltage on the integrity of the incorporated active ingredients such as therapeutic species as well as the considerable worry regarding scale up are acting to limit the popularity of the technique. The PG method outlined here would overcome both such problems and would therefore introduce a commercially feasible method for bulk production of nanofibres and nanofibre assemblies. This in turn would open the door for the realistic commercial production of a wide range of nanofibrous systems, including the three examples outlined here as well as applications such as tissue engineering scaffolds, implants. The second area of impact lies in the three areas of study outlined here. Particle-loaded nanofibrous meshes are very much in demand by various industrial sectors and their manufacture and testing are sought by many academic researchers, e.g. bioactive scaffolds, graphene precursors, antibacterial bandages/masks. In particular, the network formed via PG lends itself extremely well to wound healing applications, where particulates such as Ag may be used to promote healing and reduce infection, while the porous nature of the mesh would allow fluid transport. Therefore this research could lead to the development of a new approach to wound healing and would therefore have a significant impact on the devices and dressings industry. Oral delivery of low molecular weight drugs is a major problem facing the industry, with some 40% of new drugs having problems of solubility and bioavailability. This method would build on existing solid dispersion technologies, which have been shown to be potentially highly effective, but would also have the advantage of presenting the drug as a very high surface area to volume ration form which would further enhance dissolution, while we hypothesise that the nanoscale dimension of the meshes would be more stable to morphological changes. Freeze drying is a major and highly costly process in the pharmaceutical industry which again invariably leads to some drug loss; here we would be looking at an alternative PG method for preparing proteinaceous drugs in an easily reconstituted form but using much milder conditions than conventional lyophilization. If successful, this approach could have a major impact in terms of reducing costs associated with production and loss of active. Overall, therefore, a successful outcome to the project would have a major beneficial effect on the pharmaceutical and related industries due to the introduction of a low cost, scalable approach to manufacture of a range of commercially relevant systems. In all three cases, however, the ultimate beneficiary of the new technology would be the public, in particular patients. In particular, the development of more effective delivery systems at lower manufacturing cost will have huge knock-on health benefits, as the drugs given orally would be absorbed more effectively and hence the pharmacokinetic profiles would be more uniform and predictable, while the lower cost and reduced degradation profile of the proteins prepared using PG would have lower extraneous material and be more affordable for the taxpayer.

Publications

10 25 50
 
Description This research started in 2013-2014 and it has generated immense academic and industrial interest, and its core principles continues to evolve in different ways. It has already led to many gains:
Exploitation of using the manufacturing process investigated to produce nanofibrous pharmaceutical products, as intended from the outset.
However, several new processes have evolved:
1. Making bubbles, particularly useful in biosensing and bacterial scavenging, published and features in the leading American Chemical Society Journal LANGMUIR.
2. A sister-process, infusion controlled gyration, being exploited together with a USA partner (Kansas University) to manufacture smart nanofibres.
3. A sister-process, melt pressurised gyration, being exploited to produce non-woven tissue engineering scaffolds and anti-bacterial mats.
4. Use of the process to make a new generation of tunable bioactive shape memory mats integrated with genetically engineered proteins (collaboration with USA and China)
5. A new process - Pressure-coupled infusion gyration
6. A new EPSRC project under Healthcare on making a new generation of antibacterial filtration mats for air and water filtration with both industrial and NHS collaboration
7. New lines of work: Involving graphene - leading to a special issue to be released in J.Roy.Soc. Interface Focus later in 2018 and collaboration with Maramara University (Turkey) on novel spinning of bacterial cellulose containing bandages.
8. Led to core-sheath pressurised gyration - a new EPSRC grant (https://gow.epsrc.ukri.org/NGBOViewGrant.aspx?GrantRef=EP/S016872/1)
Exploitation Route By extending the scope of the manufacturing route to cover other essential functional materials areas, such as antimicrobial filters, wound healing bandages, making a huge impact on healthcare
Sectors Agriculture, Food and Drink,Chemicals,Creative Economy,Education,Energy,Environment,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL https://www.edirisinghelab.com/
 
Description The core manufacturing process investigated in this grant gained an exceptional altmetric score of 10, see details at: http://wiley.altmetric.com/details/1548527 This meant that many researchers and industry were interested in exploiting the process (core paper cited by >50 to date) and, in addition to the collaborating companies Astra Zeneca and BASF, two others, namely Pfizer and Colorcon, were very interested and carried out feasibility projects on exploiting this process for their products. Also, collaboration with USA and China has resulted in adapting pressurised gyration for the novel forming of "Tunable Bioactive Shape Memory Mats Integrated with Genetically Engineered Proteins" and this is featured as the front cover of the high impact international journal Macromolecular Bioscience (February 2017). Also, several other sister processes have resulted, these have also been selected to feature as front cover images of leading international journals. 1. Bubble making - Langmuir January 2015 2. Infusion Gyration - Macromolecular Rapid Communications July 2015 3. Pressurised Melt Gyration - Macromolecular Materials & Engineering August 2016 4. Pressure-coupled infusion gyration - Macromolecular Materials & Engineering June 2017, and also selected to feature in Best of Macros 2018. The work has been presented (by invitation) continuously at many international meetings, each year, from 2015, e.g. Materials Research Society (USA), Materials Science & Technology (USA) and/or The Minerals, Metals and Materials Society (USA). 5.We were delighted to win a Future Manufacturing r-mode grant to further invent our gyration processes to core-sheath manufacturing, and it has just started (Dec 2018). We have created significant impact with previous work on gyration and sister- manufacturing processes to-date, very largely due to EPSRC R-mode support mainly from the Manufacturing Portfolio. In particular, the work done in these grants (approx. to date £1.2 million and now another £300,000) have won us 11 prestigious journal front covers and two have won Best of Macros annual status, the last to-date in 2019 (just announced and selected from over 1000 papers, see below) was due to an invited feature article on these manufacturing routes which was also featured in Advanced Science News, see: https://www.advancedsciencenews.com/pressurized-gyration-for-the-mass-production-of-polymeric-fibers/ 6. We are also now using this manufacturing in antimicrobial filter making - see:https://gow.epsrc.ukri.org/NGBOViewGrant.aspx?GrantRef=EP/N034228/1, and progress on this will be reported by PI Lena Ciric under EP/N034228/1 .
First Year Of Impact 2014
Sector Agriculture, Food and Drink,Chemicals,Creative Economy,Education,Energy,Environment,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description Responsive Mode
Amount £532,537 (GBP)
Funding ID EP/N034228/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 07/2016 
End 01/2019
 
Description Responsive Mode
Amount £218,932 (GBP)
Funding ID EP/N034368/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 08/2016 
End 01/2019
 
Description Exploitation of gyratory processes uncovered at UCL for making a new generation of filters 
Organisation Gamma Healthcare
Country Unknown 
Sector Private 
PI Contribution Gyratory technology in Mechanical Engineering at UCL is being used to develop a new generation of air and water filters.
Collaborator Contribution Industrial Advisory Board
Impact Multi-disciplinary - filtration, biomedical engineering
Start Year 2016
 
Description Exploitation of gyratory processes uncovered at UCL for making a new generation of filters 
Organisation Great Ormond Street Hospital (GOSH)
Country United Kingdom 
Sector Hospitals 
PI Contribution Gyratory technology in Mechanical Engineering at UCL is being used to develop a new generation of air and water filters.
Collaborator Contribution Industrial Advisory Board
Impact Multi-disciplinary - filtration, biomedical engineering
Start Year 2016
 
Description Exploitation of gyratory processes uncovered at UCL for making a new generation of filters 
Organisation Intrinsiq Materials Ltd
Country United States 
Sector Private 
PI Contribution Gyratory technology in Mechanical Engineering at UCL is being used to develop a new generation of air and water filters.
Collaborator Contribution Industrial Advisory Board
Impact Multi-disciplinary - filtration, biomedical engineering
Start Year 2016
 
Description Exploitation of gyratory processes uncovered at UCL for making a new generation of filters 
Organisation PALL Europe
Country United Kingdom 
Sector Private 
PI Contribution Gyratory technology in Mechanical Engineering at UCL is being used to develop a new generation of air and water filters.
Collaborator Contribution Industrial Advisory Board
Impact Multi-disciplinary - filtration, biomedical engineering
Start Year 2016
 
Title Antimicrobial filter 
Description EPSRC healthcare responsive mode grants and industrial and NHS support to make a new generation of antimicrobial water and air filters. 
Type Preventative Intervention - Physical/Biological risk modification
Current Stage Of Development Initial development
Year Development Stage Completed 2017
Development Status Under active development/distribution
Impact Reduce/eliminate microbial activity in key public places 
 
Title Vaginal drug delivery 
Description Making a tampon for vaginal delivery of progesterone 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2017
Development Status Under active development/distribution
Impact Addressing the concerns of pre-term birth, especially in Africa 
 
Title Wound healing bandages 
Description Gyro-spinning wound healing bandages containing specialised materials 
Type Therapeutic Intervention - Physical
Current Stage Of Development Initial development
Year Development Stage Completed 2018
Development Status Under active development/distribution
Impact Bacterial cellulose (BC) is a very promising biological material. However, at present its utilization is limited by difficulties in shape forming it. In this Communication, it is shown how this can be overcome by blending it with poly(methylmethacrylate) (PMMA) polymer. BC:PMMA fibers are produced by pressurized gyration of blended BC:PMMA solutions. Subsequently, BC:PMMA bandage-like scaffolds are generated with different blends. The products are investigated to determine their morphological and chemical features. Cell culture and proliferation tests are performed to obtain information on biocompatibility of the scaffolds. 
URL http://onlinelibrary.wiley.com/doi/10.1002/mame.201700607/full
 
Description Key USA conferences such as TMS, MS&T and MRS -keynote/invited, annual invited participation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Sessions dedicated to novel manufacturing routes for biomedical engineering
Year(s) Of Engagement Activity 2015,2016,2017
URL http://www.ucl.ac.uk/~ucemmje/