ADVANCED FLOW TECHNOLOGY FOR HEALTHCARE MATERIALS MANUFACTURING

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

Abstract

Inorganic nanoparticles have the potential to dramatically modify existing materials while providing the capability to engineer a broad range of transformative new products. Exhibiting unique properties not encountered in bulk materials, inorganic nanoparticles present the opportunity to address, and the potential to overcome, some of the most pressing global challenges. This is leading to intense global competition to develop and commercialize nanoproducts with a variety of applications in healthcare, energy, transport and security, with the aim of acquiring a dominant market position in the nanotechnology sector. Nanoparticles offer ideal solutions for detecting and treating many diseases. They can be used as drug carriers, labelling and tracking agents, and vectors for gene therapy, hyperthermia treatment and magnetic resonance imaging contrast agents. Used as targeted drug-delivery systems, they can improve the performance of medicines already on the market. They enable the development of new therapeutic strategies such as anti-cancer drug delivery, extending product life cycles and reducing healthcare costs. In this proposal we focus on the manufacturing of gold nanoparticles (Au-NPs) and iron oxide magnetic nanoparticles (MNPs). These materials have existing applications in diagnostics and therapeutics. Bespoke monodispersed functionalised NPs offer new applications in antimicrobial surfaces (Au NPs plus dye) and in a new hyperthermia treatment for cancer (MNPs). UCL is at the forefront of the engineering approach to make nanoparticles as well as being world leading in magnetic hyperthermia and antimicrobial surfaces.

Nanoparticles are conventionally synthesized in relatively small batch reactors. These systems are poorly controllable, leading to products that are hard to reproduce. Also, they do not lend themselves to expedient upscaling. Such problems are caused by the inefficient mixing and slow heat and mass transfer characterizing batch reactors, and by the difficulty of decoupling in time the various stages of the synthesis, particularly particle nucleation and growth. This research aims to design and demonstrate a new, sustainable and scalable approach for manufacturing high-value nanomaterials with advanced properties in a way that is controllable and reproducible and that does not involve significant upscaling issues. To attain this ambitious goal, we will integrate methods, skills and strengths of different disciplines (materials chemistry, engineering), seeking guidance from industrial partners and UK manufacturing centres. Giving us access to their state-of-the-art facilities, sharing their expertise and providing an application context for our work, they will further characterize the nanoparticles, evaluate their performance and facilitate pathways to manufacture and routes to market.

There is currently a lot of research in developing novel materials, where the focus is on discovery but with little emphasis on manufacturing. Using chemical engineering principles and systems engineering methodologies within a multidisciplinary framework, our research will demonstrate not only the need to consider key physical phenomena (mixing, heat transfer etc.) in nanoparticles synthesis, but also how to account and address related manufacturing challenges from the outset. In this way, an important benefit of this project will be to provide a paradigm shift in nanoparticle synthesis and production and bridge the discovery-manufacturing divide.

Planned Impact

Impact on economy. Nanotechnologies are important to the UK future because of their potential to improve, if not altogether transform, many types of consumer products. The worldwide transition toward the use of nanotechnologies is a significant economic opportunity for the UK. In healthcare, nano-enabled drug delivery is expected to grow from a current value of $2.3 billion to $136 billion by 2021, while nano-enabled diagnostics is estimated to reach $53 billion by 2021. This work will contribute to keeping the UK at the forefront of nanotechnology by enhancing UK's strategic manufacturing capability. Although the research focuses on healthcare applications, our technology will have wide applicability and impact, and will naturally translate to other manufacturing sectors. The nanotechnology industry in general will thus benefit from this work. Our approach will help reduce risk and capital cost associated with scaling up, by eliminating costly redesigns and pilot plant experiments.

Impact on society. In the long term, the health and life quality of the wider public will benefit through the provision of more efficient and less harmful diagnostic and therapeutic techniques enabled by the use of the nanomaterials that this research aims to manufacture. Nanoparticles offer the opportunity to radically change how we prevent, diagnose and treat diseases through ground-breaking advances in targeted and time-controlled drug delivery, radiotherapy, cancer treatment and regenerative tissue engineering. However, to make this vision a reality, we need to engineer robust and scalable processes able to manufacture NPs consistently and with the desired throughput. This research will enable us to achieve this, contributing to making such products viable to the general public. Should this technology become established and readily available, it will greatly benefit the society at large, improving life-quality and life-expectancy.

Impact on knowledge. Integrating methods, skills and strengths of different disciplines, this interdisciplinary project will yield new knowledge of value to researchers and manufacturers involved in nanoscience and biomedicine. This work will assist them - both in industry and academia - to better understand, predict and control nanoparticle synthesis processes and to produce advanced functionalized nanomaterials reproducibly. Our industrial partners will directly benefit by actively engaging in the development of this technology, acquiring knowledge on fundamental aspects of continuous-flow nanoparticle synthesis and engineering, and being able to evaluate early this technology. By widely disseminating this work, we will help the broader community of scientists, engineers and manufacturers working in this area to understand this technology and realize its potential.

Impact on people. The researchers involved in this project will be highly trained in a wide range of areas, including nanotechnology, materials chemistry, flow chemistry, chemical engineering and microfluidics. They will bolster their ability to work in a highly interdisciplinary environment independently and in a team, acquiring technical and transferable skills that will enhance their professional development and employability.

Publications

10 25 50
 
Description Three different categories of nanoparticles are targeted: 2nm gold nanoparticles that find application in antimicrobial materials and coatings, 20-40 nm gold nanoparticles for diagnostics and iron oxide nanoparticles that are attractive for cancer hyperthermia. Regarding the 2 nm gold nanoparticles, the high-throughput synthesis of Au25 clusters (sub-2 nm, ~1 gAu/day) has been developed with a continuous flow system. The synthesized Au clusters have demonstrated excellent antimicrobial activity. Another manufacturing route for ~2 nm gold nanoparticles has been translated from batch processes. In terms of the continuous flow synthesis of 20-40 nm gold nanoparticles, a two-phase flow open-loop reactor system has been developed for the continuous manufacturing of targeted gold nanoparticles, and the coupled online UV-Vis spectrometer in the system allowed online quality mointoring of the Au nanoparticles.
Continuous flow reactors in combination with x-ray scatttering techniques facilitated novel insights into the particle formation mechanism of iron oxide nanoparticles synthesized via the aqueous co-precipitation method. The gained knowledge was essential for the design of continuous reactros for manufacturing, and made it possible to synthesize ~5 nm particles (which is considered as a promising size for MRI T1 contrast agents) using cost effective methods.
Exploitation Route Translating these batch processes into continuous flow manufacturing processes can benefit companies to continuously synthesize functional nanoparticles with control over their size and their properties. Additionally, the antimicrobial manufacturing methodologies developed are of great interest to relevant industries dealing with antimicrobial coatings and membranes for hospital and healthcare use.
The methods developed to study particle formation kinetics facilitated via flow reactor designs answered many questions on the growth mechanism of co-precipitation of iron oxide nanoparticles guiding future synthesis and allowing for further optimization based on the better understood particle formation kinetics.
Sectors Chemicals,Healthcare,Manufacturing, including Industrial Biotechology

 
Description This project has been in close engagement with University College London Hospitals (UCLH). The outcome of our research has a potential application in hospital and healthcare use, especially for antimicrobial surfaces. The continuous processes gold nanoparticles synthesis we have developed in this project, which can help reduce risk and capital cost associated with scaling up and facilitate routs to market, can be employed by UK nanotechnology industry. Potential cooperation is under discussion with nanoparticle and antimicrobial materials manufacturing companies utilising the developed methods for the continuous production of gold nanoparticles. Academic collaborations have been established for the study of the catalytic activities and the relaxivity for MRI contrast agent candidates or iron oxide nanoparticles manufactured using continuous methods.
First Year Of Impact 2019
Sector Healthcare
Impact Types Societal,Economic

 
Description Centre for Nature Inspired Engineering, inspiration grant: Nature Inspired Green, Tuneable & Scalable Synthesis of Magnetic Nanoparticles
Amount £26,120 (GBP)
Organisation University College London 
Sector Academic/University
Country United Kingdom
Start 02/2019 
End 11/2019
 
Description 29th European Conference on Biomaterials: "Continuous Flow Synthesis of Gold Nanoparticles for Biomedical Applications" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact C. Körner, H. Huang, M. O. Besenhard, A. Gavriilidis, T. Luxbacher, "Continuous Flow Synthesis of Gold Nanoparticles for Biomedical Applications", 29th European Conference on Biomaterials, ESB2018, Maastricht, 9-13 September 2018, Poster presentation.
Year(s) Of Engagement Activity 2018
 
Description 8th CBM Workshop "Sub- 5 nm Gold Nanoparticle Synthesis by the Turkevich Method in a Microfluidic System" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Presentation given at 8th Workshop "Chemical and Biological Micro Laboratory Technology", Ilmenau/Elgersburg, Germany, 23-25 February 2016. Presentation title: H. Huang, R. Baber, H. Du Toit, I. Parkin, A. Gavriilidis, "Sub- 5 nm Gold Nanoparticle Synthesis by the Turkevich Method in a Microfluidic System"
Year(s) Of Engagement Activity 2016
URL https://www.tu-ilmenau.de/mrt/cbm-workshops/8-cbm-workshop-2016/
 
Description AIChE 2016: "Study on Gold Nanoparticles Flow Synthesis in a Microwave-Assisted Reactor" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Oral Presentation
M. K. Bayazit, S. P. Damilos, E. Cao, A. Gavriilidis, J. Tang, "Study on Gold Nanoparticles Flow Synthesis in a Microwave-Assisted Reactor", AIChE Annual Meeting, San Francisco, November 2016.
Year(s) Of Engagement Activity 2016
URL https://www.aiche.org/conferences/aiche-annual-meeting/2016
 
Description COST - RADIOMAG2017 Poster presentation - Continuous Syntheses of Iron Oxide Nanoparticles for Large Scale Production 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster Presentation:
Maximillian O. Besenhard, Alec P. LaGrow, Katerina Loizou, Nguyen T. K. Thanh, and Asterios Gavriilidis
Year(s) Of Engagement Activity 2018
 
Description Dept of Chemical and Biological Engineering, HKUST: "Nanoparticle Synthesis in Flow", 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Seminar: A. Gavriilidis, "Nanoparticle Synthesis in Flow", Dept of Chemical and Biological Engineering, HKUST, Hong Kong, 5 December 2018.
Year(s) Of Engagement Activity 2018
 
Description IChemE Particle Technology Special Interest Group meeting January 2017: "Nanoparticle and Microparticle Production in Flow" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Oral presentation A. Gavriilidis, L. Mazzei, "Nanoparticle and Microparticle Production in Flow", IChemE Particle Technology Special Interest Group meeting, London, 23 January 2017.
Year(s) Of Engagement Activity 2017
URL http://www.icheme.org/communities/special-interest-groups/particle%20technology/events/2017/agm-23ja...
 
Description IMRET 14, "Continuous Synthesis of Gold Nanoparticles with Carbon Monoxide in Segmented Flow System" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Oral presentation
H. Huang, H. du Toit, R. Baber, I. Parkin, A. Gavriilidis, "Continuous Synthesis of Gold Nanoparticles with Carbon Monoxide in Segmented Flow System", 14th International Conference on Microreaction Technology, Beijing, China, 11-14 September 2016.
Year(s) Of Engagement Activity 2016
 
Description IMRET 14, "Controlling Nucleation using UV Light for the Synthesis of Citrate Capped Gold Nanoparticles" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Oral presentation
H. du Toit, T. Macdonald, H. Huang, L. Mazzei, I. Parkin, A. Gavriilidis, "Controlling Nucleation using UV Light for the Synthesis of Citrate Capped Gold Nanoparticles", 14th International Conference on Microreaction Technology, Beijing, China, 11-14 September 2016.
Year(s) Of Engagement Activity 2016
 
Description IMRET 14, "From Batch to Flow: Developing our Understanding of Multiphase Reaction Systems for the Synthesis of Thiol Stabilised Gold Nanoparticles in Continuous Flow" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation
H. du Toit, T. Macdonald, I. Alissandratos, C. Makatsoris, I. Parkin, A, Gavriilidis, "From Batch to Flow: Developing our Understanding of Multiphase Reaction Systems for the Synthesis of Thiol Stabilised Gold Nanoparticles in Continuous Flow" , 14th International Conference on Microreaction Technology, Beijing, China, 11-14 September 2016.
Year(s) Of Engagement Activity 2016
 
Description MRS Spring Meeting 2016, "Size Controlled Synthesis of Gold Nanoparticles Using Light Induced Reduction" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation
H. du Toit, T. Macdonald, I. Parkin, A. Gavriilidis, "Size Controlled Synthesis of Gold Nanoparticles Using Light Induced Reduction " 2016 MRS Spring Meeting, Phoenix, Arizona, March 2016.
Year(s) Of Engagement Activity 2016
URL http://www.mrs.org/spring2016
 
Description UK Colloids 2017: "Continuous Flow Synthesis of Iron Oxide Nanoparticles" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Oral Presentation: A. LaGrow, M. Besenhard, A. Gavriilidis, N. Thanh, "Continuous Flow Synthesis of Iron Oxide Nanoparticles", UK Colloids 2017, Manchester, 10-12 July 2017.
Year(s) Of Engagement Activity 2017
 
Description WWCE10: "Optimizing Nanoparticle Synthesis via Flow Chemistry" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Oral Presentation: M. Besenhard, A. LaGrow, N. Thanh, A. Gavriilidis, "Optimizing Nanoparticle Synthesis via Flow Chemistry", 10th World Congress in Chemical Engineering, Barcelona, Spain, 1-5 October, 2017.
Year(s) Of Engagement Activity 2017
 
Description e-MRS Spring Meeting 2016, "Sub- 5 nm Gold Nanoparticle Synthesis by the Turkevich Method in a Microfluidic System" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation
H. Huang, R. Baber, H. Du Toit, I. Parkin, A. Gavriilidis, "Sub- 5 nm Gold Nanoparticle Synthesis by the Turkevich Method in a Microfluidic System", e-MRS, European Materials Research Society Spring Meeting 2016, Lille, France 2-6 May 2016.
Year(s) Of Engagement Activity 2016
URL http://www.european-mrs.com/meetings/2016-spring-meeting