Phosphate Bio-mineral-Ultrafast Laser interaction - a pathway for future hard tissue re-engineering (Novel Tool for Surgical technologies) - LUMIN

Lead Research Organisation: University of Leeds
Department Name: Chemical and Process Engineering

Abstract

Acid erosion due to food and drink intake in particular and tooth surface loss due to general wear of the dentition is a global problem. Continual erosion and loss of the surface enamel of the tooth leads to hypersensitivity. This oral condition is acute in both children and the ageing population of society and can have a significant impact on the quality of life. The 2011 census points out that 16.3% of the population of England and N Ireland is above 65 years old (Daily Telegraph 17 July 2012), which suggests that the number of people suffering from acid erosion may continue to rise in years to come. This means that there is an even more urgent need to provide a robust solution for restoring lost enamel, a problem that remains intractable for clinical dentistry. To address this problem, we propose research into an engineering methodology to spray the tooth with a thin mineral layer that is then densified and bonded to the underlying tooth using an ultrafast laser irradiation pulse.
The cross-disciplinary LUMIN project will develop and exploit the technology of micro-nozzle bio-mineral delivery in Task (a) and its subsequent sintering using femto-second pulsed (fsp) lasers for the restoration of acid-eroded enamel. The operating wavelength of the proposed fsp lasers will be in the eye-safe regions of the near-IR (1500-2100 nm) and will offer flexibility in terms of energy/power delivery by engineering the laser cavity, which is the main goal of Task (b). An additional goal of Task (b), as stated in the objective section above, is to integrate the micro-nozzle bio-mineral delivery system from Task (a) with lasers on a single platform for achieving rapid sintering in the deposited bio-mineral layers on to the acid-eroded enamel surface. During this research, novel acid-resistant enamel mineral substitutes, in crystalline and gel forms, will be engineered and optimized for the micro-nozzle delivery in Task (a). The integration of the materials delivery system with the fsp-laser will then yield simultaneous sintering.. The engineering approaches herein will therefore yield 3 different platform technologies for future exploitation, which will be achieved with the support from the Integrated Knowledge Centre on Tissue Engineering and Medical Technologies at Leeds.
We will investigate whether the use of a micro-nozzle for gel and suspension materials with an fsp-laser poses a risk of toxicity due to generation and release of nano-scale particulates (some may argue these might be photosensitized by the intense beam of the fsp-laser). In Task (c) we will therefore assess any nano-particle and photo-induced toxicity and perform a risk analysis. This will conform to standard clinical procedures with an aim to thus identify and minimise any imminent risk.
Following Task (c), our goal in Task (d) is to implement the engineering approaches, developed in Tasks (a) and (b) together with the risk mitigation strategy in Task (c) for testing fsp-laser sintered enamel minerals in the oral environment using in-situ mouth appliance trials, a technique pioneered at the Leeds Dental Institute to minimising the risks in extensive in-vivo trials. In Task (d) the sintered materials will be characterised for acid erosion, durability, hardness, toughness, and flexural bend with using the assembled academic expertise in materials science and engineering and clinical dentistry.
The IKC team will provide support, via Dr. Graeme Howling's expertise, to develop technology exploitation through the project partners, M-Squared Lasers, British Glass, and Giltec in the first instance. The project also aims to establish academic links with overseas academic institutions e.g. the IMI at Lehigh and Penn State in Materials Science, and with Stanford and Caltec in the US via the SUPA led EPSRC funded collaboration. The industry-academia link with the Photonics KTN in the UK is also expected to develop during the course of project.

Planned Impact

The project we propose has a clear strategy to deliver impact at multiple levels from the development of new ideas and devices of interest to the academic community to the delivery of new treatment options which may be of relevance to millions of dental patients both within the UK and worldwide. In order to achieve this impact, we have developed a strategy based on the background and foreground of IP and close collaboration with relevant companies within the field. In order to deliver maximum impact we also plan to have a specifically dedicated impact manager with a role focussed on identifying and nurturing new opportunities for our technology.
Within our proposed work plan, tasks (a) to (d) will deliver engineering appliances and the methodologies for protecting and restoring enamel minerals, from which initially clinical dentistry will directly benefit, with the clear potential for this work to be extended to cosmetic dentistry at a later stage. The current research is of preclinical nature, we will gain sufficient data through toxicity testing, risk analyses and oral appliance tests for progressing into in-vivo trials soon after the project finishes. In task d) the chosen volunteers for in-situ mouth appliance tests will also provide feedback on new technology, supporting future development and technology acceptance for patient care. A letter of support from LDI, stating the link with the NHS Trust, the stakeholder is included.
Although the research focusses on development of engineering platform technologies, wider impact over longer period is anticipated through background and foreground patents for orthopaedics and bone related diseases and for micro- and nano-scale , photonics, and semiconductor materials fabrication and device engineering.
NEW KNOWLEDGE: Our background research and publications evidence examples of materials structural changes using continuous wave and ultra-fast laser irradiation of minerals. As a result a new subject area within the field of lasers and materials science has emerged and is likely to grow, clearly giving "world-first" status for the academic research. The two academic partners from the UK are well positioned to lead the field and develop expertise for applications in medicine and other non-medicinal surface modification and engineering. The patents and knowledge transfer activities, stated in the proposal, will directly benefit 3 UK industries involved (M-Squared Lasers and British Glass), and Giltec (currently under discussion). The letters of support and contributions offered by our company partners demonstrate industrial commitment. Revenue from future licensing will help the academic research to grow at Leeds and St Andrews and will help progress the emerging ideas for orthopaedic and non-medicinal applications, as stated above. WE ANTICIPATE NOVEL MANUFACTURING AND DEVICE ENGINEERING AND TECHNOLOGY TO GROW FROM THE PROPOSED RESEARCH.
Our initial plan is to work with the project partners for developing the component and integrated platform technologies to a point so that the licensing to larger medical appliance companies becomes feasible. Commercialisation support from Dr Graeme Howling, our impact manager, at the Integrated Knowledge Centre in Tissue Engineering and Medical technologies at Leeds will help in accelerating the process of wider exploitation through relevant industrial conduits.
High quality interdisciplinary research papers are expected from the research that we aim to publish via the regular peer-review channel and from which the rest of the academic and industrial community will benefit. A workshop to which interested parties will be invited at the end of the project will showcase our technologies to the wider academic and commercial domain.
PEOPLE BENEFIT: Successful clinical translation through in-vivo trials in future will provide potentially "pain free dental care" for patients worldwide which will be a major success story for the project.

Publications

10 25 50
 
Description The EPSRC project is focussed on developing novel acid resistance minerals for enamel restoration. Within 1 year the project has discovered new enamel mineral and designed the delivery system, which is now being tried ex vivo for bovine incisors using ultrafast laser developed at St Andrews University. Toxicity aspects of minerals have been analysed. The tests so far reveals that the minerals are safe in oral environment. Ex vivo erosion tests will commence soon which will pave path for in-situ mouth appliance trials. The complementary EU funded project is helping to develop the technology. The project ends in Dec 2016.
The project has contributed to developing a new area of research on bone materials processing. The EPSRC and accompanying EU grants have created a road map for materials manufacturing and integration for tissue engineering. Alpha version of medical device was designed and it is tested for ex vivo enamel restoration in 2017. In the end December we demonstrated the proof-of-concept of the medical device.
In 2018 April we applied for new project based on the success of the EPSRC (LUMIN), EU-LUSTRE, and EU-PReFaCTO proejcts to propose next generation of medical device design in a new Innovate UK funded project Apollinia, which was successful and it will conclude Dec 2020. The project is integrated with the IKC project in which we have selected 23 volunteers for testing in situ mouth appliance on to which novel enamel materials will be mounted for testing in the oral environment. The new medical device has integrated OCT, IR thermometry, laser for sintering, and materials delivery system which are all being tested.
Plan for CE marking is also in place for the medical device.
Relevant research papers and patents are available via links on Google Scholar.
Exploitation Route The Apollinia Project (133651) is a good platform for realizing the integrated medical device for progressing and planning of tooth surface loss experiments. A future project is in planning which is going to be led by Attenborough Dental in Nottingham.
Sectors Chemicals,Healthcare,Manufacturing, including Industrial Biotechology

URL https://gtr.ukri.org/projects?ref=133651
 
Description Concept in Confidence Medical Research Council (CiC-MRC)
Amount £600,000 (GBP)
Organisation University of Leeds 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 09/2018
 
Description Doctor Training Grant
Amount £65,000 (GBP)
Funding ID Neelam Iqbal 
Organisation University of Leeds 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 03/2020
 
Description EU Marie Curie IAPP LUSTRE project
Amount € 2,444,500 (EUR)
Funding ID MC-IAPP-2013-LUSTRE 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 03/2014 
End 12/2017
 
Description H2020 SC1-2019-Single-Stage-RTD SBR Grant agreement no: 874896
Amount € 6,450,000 (EUR)
Funding ID H2020 SC1-2019-Single-Stage-RTD SBR Grant agreement no: 874896 
Organisation EU Health Programme 
Sector Public
Country European Union (EU)
Start 01/2020 
End 12/2023
 
Description IKC proof of concept awards
Amount £10,000 (GBP)
Funding ID Periodontal Restoration Using Femtosecond pulsed lasers (PRUF) 
Organisation University of Leeds 
Department Medical Technologies IKC
Sector Academic/University
Country United Kingdom
Start 09/2016 
End 09/2017
 
Description INNOVATE UK (FASTIC)
Amount £126,156 (GBP)
Funding ID TS/L003988/1 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 12/2013 
End 11/2015
 
Description Marie-Curie IIF
Amount € 220,000 (EUR)
Funding ID BoNE-GrAFT 
Organisation European Union 
Sector Public
Country European Union (EU)
Start 11/2017 
End 10/2019
 
Description PRe-FaCTO Marie Curie Incoming Fellowship
Amount € 220,000 (EUR)
Funding ID 660147 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2016 
End 12/2017
 
Description Royal Commission of 1851 Industrial Fellowship
Amount £119,042 (GBP)
Organisation Royal Commission for the Exhibition of 1851 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2017 
End 12/2020
 
Description TS/S002022/1
Amount £855,000 (GBP)
Funding ID TS/S002022/1 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 12/2018 
End 11/2020
 
Description ULTRA-GLASS
Amount £730,000 (GBP)
Funding ID TS/P013449/1 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 08/2017 
End 07/2019
 
Title LUMin Surgical Device - Prototype 
Description In collaboration with the industry partners (M-Squared Lasers in UK, ICMEA in Bari Italy) we have developed a novel surgical tool for restoring enamel. This device has a materials and laser delivery system for in vitro experiments which aims to precisely fix the damaged enamel. In vitro trials along with in situ mouth appliance trials are under investigation at the University of Leeds. The laser equipoment has been contributed by M-Squared Lasers which was developed together with the collaboration with the University of St. Andrews. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Provided To Others? No  
Impact The patented medical device will make impact in the area of restorative dentistry as a whole. 
 
Title Prototype of the laser-Materials delivery system for restoring enamel 
Description The integrated laser power-materials delivery system is commissioned for in vitro trials on human and bovine enamels. Restored human enamel in vitro enamels will be tested for in situ mouth appliance trials in human volunteers for testing the resurfaced enamel inder oral challenges. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2017 
Provided To Others? No  
Impact Test is in progress 
 
Description BoNE-GraFT EU Fellowship 
Organisation Leeds General Infirmary
Country United Kingdom 
Sector Hospitals 
PI Contribution Leeds General Infirmary (Prof. P. Giannoudis) LIRMM (Dr. Elena Jones) New collaboration
Collaborator Contribution The project aims to develop a strong cortical bone templates for integrative manufacturing of bone tissues.
Impact New collaboration
Start Year 2017
 
Description DTC Collaborative PhD Studentship 
Organisation Leeds General Infirmary
Country United Kingdom 
Sector Hospitals 
PI Contribution A collaborative partnership for research on physiological engineering of bone has been supported by the University with the LIRMM and LGI. Ms Neelam Iqbal is a new CASE PhD student.
Collaborator Contribution The orthopaedic tissue testing and imaging facilities are located at LIRMM and LGI, which will be utilized in the project for ascertaining the injury. Prof. Peter V Giannoudis is the main clinical supervisor who works closely with a bone biologist (Dr Elena Jones). The supervision in the area of physiological engineering of bone will involve imaging, prototyping the structure of tissue and then fabrication for designing bone which will be testing in a small animal model.
Impact The PhD student is writing her first paper at present on laser-chitosan mineral interaction.
Start Year 2016
 
Description Exogenous mineralisation 
Organisation M Squared Lasers Ltd
Country United Kingdom 
Sector Private 
PI Contribution £45000
Collaborator Contribution Equipment loan - the company has loaned femto-second laser for trials at Leeds for exogenous mineralisation. M-Squared Lasers
Impact Not yet as the project only begun in Nov 2017
Start Year 2017
 
Description IKC Tissue Engineering Leeds for periodontium tissue engineering 
Organisation University of Leeds
Department Medical Technologies IKC
Country United Kingdom 
Sector Academic/University 
PI Contribution The IKC Tissue Engineering team has funded a seed-corn project to support the Marie-Curie Fellowship project of Dr. Antonios Anastasiou. This short-term project is linked with main stream Marie-Curie PReFacto project at Leeds. In this project, the cell growth study is being carried out for ascertaining the suitability of laser-irradiated chitosan/calcium phosphate minerals for engineering a novel tissue template for restoring damaged periodontium.
Collaborator Contribution IKC is funding the seedcorn project.
Impact Not yet
Start Year 2016
 
Description MRC-CiC 
Organisation University of Leeds
Department Faculty of Medicine and Health
Country United Kingdom 
Sector Academic/University 
PI Contribution long bone materials manufacturing and animal trials
Collaborator Contribution Surgical technologies and biomechanics of long bone
Impact Not yet
Start Year 2016
 
Description Royal Commission of 1851 Industrial Fellowship 
Organisation University of Leeds
Department Leeds Institute of Rheumatic and Musculoskeletal Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution The project partnership is for physiological engineering of load-bearing (long) bones and its biomechanics. A new integrative manufacturing apporach is developed for long bones for finding a synthetic bone substitute that is compatible with the human and mamallian physiology.
Collaborator Contribution Contributions are in the area of novel surgical technologies
Impact Not available
Start Year 2015
 
Description SBR-EU project 
Organisation University of Patras
Country Greece 
Sector Academic/University 
PI Contribution This collaboration is a part of the new EU project on Stimulated Bone Regeneration which started in Jan 2020. This is a multi-partner (10 partner) research consortium on restoring large bone defects.
Collaborator Contribution Partners are expected to provide: a) Specification on bone materials fabrication b) pharmacology c) biomechanics
Impact Not yet
Start Year 2020
 
Title FORMULATION 
Description The present invention relates to a hydrogel formulation in which the solid phase is composed of a continuous network of siloxane bonds and one or more calcium phosphate phases doped with one or more metal dopants. 
IP Reference WO2016046517 
Protection Patent application published
Year Protection Granted 2016
Licensed Commercial In Confidence
Impact The patent has enabled the fabrication of templates for restoring damaged periodontal tissue and physiological engineering of bone materials. Novel manufacturing technologies are emerging for in-theatre manufacturing of tissues for in-patient use.
 
Title Sinter Coating Tool 
Description A medical device has been designed for sinter coating the dental enamel. This is a platform technology which is also protected for bone tissue engineering and restoration for in-theatre use. 
IP Reference  
Protection Copyrighted (e.g. software)
Year Protection Granted 2017
Licensed Commercial In Confidence
Impact Development of bone manufacturing and, fixing periodontal tissue damage.
 
Company Name VitriTech Ltd 
Description The company specializes in the area of manufacturing laser glasses and finished gain medium, phosphate materials for biological and cosmetics applications. The company acquired IP for expanding its business in health area. It is currently working on collaborative research with GTS in Chapeltown Sheffield and the University of Leeds in a joint research projects related with medical devices. 
Year Established 2015 
Impact Technology for laser gain manufacturing has been licensed to this company from the University of Leeds.
Website http://www.vitritech.co.uk/
 
Description Bone & Enamel Tissue Science & Engineering 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was a new one day meeting which we launched to start a platform for discussion. Clinician, industry partners, students and researchers, publishers engaged in this one day meeting which was sponsored by the industry partners.
Year(s) Of Engagement Activity 2017
URL http://www.betse2017.org/
 
Description International Conference on Optical, Optoelectronic, Photonic Materials and Applications (ICOOPMA) - Invited talk 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I am one of the founding members of the biennial ICOOPMA Conference series. In this conference the Biophotonics part was included at the 2014 event at the University of Leeds. This session expanded in the 2016 event at Montreal. I gave an invited talk on the Restoration of Damaged Enamel using Ultrafast Lasers. This conference attracts exceptional speakers including Nobel Prize winners and world leading experts. Biophotonics will be featured strongly in the Brazil meeting in 2018.
Year(s) Of Engagement Activity 2016
URL http://icoopma2016.org/
 
Description International Congress on Glass (Shanghai) Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The ICG is a significant event in the American Ceramic Society. The symposium has several technical committee, in which Biomaterials and Optoelectronics are two main technical committees (TC) in which I have main interest. I am member of the TC20 on Optolectronics Committee. I have led the research on the applications of mode-locked lasers for the processing of biomaterials. In the Biomaterials Symposium I gave an Invited talk.
Dr Antonios Anastasiou was the lead participant.
Year(s) Of Engagement Activity 2016
URL http://www.icg2016shanghai.com/dct/page/65566
 
Description Keynote Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The Society of Glass Technology holds annual conference in UK in which international participants present their work. In a 3-day International Meeting I gave a Keynote Lecture on the Phase Transformation in Calcium Phosphate based gels and colloids. The results from the EPSRC and EU funded projects were presented. I explained the mechanism of ultra-fast phase transformation arising as a result of irradiation from near-IR mode-locked lasers.
A new approach for studying the phase transformation was studied and analysed by using thermal analysis techniques.
Year(s) Of Engagement Activity 2015
URL http://www.glassreflections.sgt.org/