Development of a Novel, Safe Method for the Non-invasive Assessment of Human Bone Quality, In Vivo, using spatially offset Raman spectroscopy.

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

Abstract

The proposed activity is part of an exciting programme of international and multi-disciplinary work developing Raman spectroscopy of skeletal tissues for clinical use; measured for the first time through the unbroken skin. We are initially targeting bone in patients with osteoporosis, but this novel technology is applicable to other tissues and conditions. This project will add value to our work with three major associated developments: optimisation of bone spectroscopy through skin (both temporally and spatially-resolved techniques); identification of major spectral features that are associated with bone strength; and improving fracture risk predictions in comparison to the current standard DXA scans. A major problem our Society faces as a consequence of continual advances in healthcare and increasing wealth is enhanced life expectancy. With this the ability to enjoy a healthy and active ageing is often compromised by painful long lasting degenerative diseases of the musculoskeletal system. Indeed the Government is keen on prevention through ealry diagnosis and lifestyle changes, health ageing is a National Government priority.Current techniques used to identify the major degenerative skeletal diseases such as osteoarthritis and osteoporosis are based on imaging using X-ray radiation (DXA scanning, CT scans and Radiography). These technologies are limited as they rely on imaging the mineral component of the bone tissue, the mechanical strength of bone,however, is determined largely by the protein component, predominantly collagen type I and this is invisible to X-ray techniques.Bone tissue is a composite material comprising an inorganic mineral crystal component and an organic proteinaceous fibre component. The mineral fraction largley determines the stiffness of the material and the fibre component the strength.Many bone diseases and age related changes to the skeleton arise as a consequence of changes in the protein chemistry, either as a consequence of the genetic make up of an indivudual or the mechanical loading of the bone itself.Recently our collaborative team has developed a new revolutionary technique capable of determining bone tissue composition non-invasively through patients' skin. The concept, Spatially Offset Raman Spectroscopy (SORS), enables safe characterisation of tissue in vivo at depths of several millimetres. This is by at least an order of magnitude deeper than that possible with conventional Raman methods. Our breakthrough paves the way for the development of safe techniques for the early diagnosis of diseases where subtle molecular details within tissue can provide indicators of health problems, for example, the non-invasive diagnosis of genetic bone disease such as brittle bone disease and degenerative conditions such as arthritis. Other analytical applications include the probing of pharmaceutical products in depth and through coatings and packaging, the subsurface probing of paints, food products and security screening. The research project is enhanced through a strong cross-disciplinary science component opening a new branch of Raman spectroscopy with strong potential for commercial exploitation of research outcomes. Our research has permitted us to obtain the first Raman spectra of human bone in vivo under totally safe conditions (2 mW) as a basic proof of concept. Although as yet unoptimised the available information can be contrasted with that obtainable using conventional X-ray techniques such as DEXA which only yield the density of the mineral component. The extra information contained in Raman spectra holds promise for the characterisation of bone diseases such as osteoporosis or brittle bone disease. To realise this goal, further research is now needed to increase the penetration depth and establish a firm link between Raman spectra and specific bone diseases. This proposal has the potential to develop a new diagnostic modality in modern medicine.

Publications

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Bergström I (2017) Compressive loading of the murine tibia reveals site-specific micro-scale differences in adaptation and maturation rates of bone. in Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA

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Buckley K (2011) Recent advances in the application of transmission Raman spectroscopy to pharmaceutical analysis. in Journal of pharmaceutical and biomedical analysis

 
Description Please explain for a non-specialist audience what has been discovered or achieved as a result of the work funded through this award. *
A clinical study was set up, with appropriate ethical and MHRA approvals, at the Royal National Orthopaedic Hospital, Stanmore, UK. The aim of the research was to assess the potential of Spatially offset Raman spectroscopy (SORS) as a tool for the exploration (and potential diagnosis) of bone disorders, namely osteoporosis, osteoarthritis and osteogenesis imperfecta. In total c. 150 patients and control volunteers were assessed and Raman signatures were acquired for analysis. . The study aimed to explore the chemistry of bone matrix in different bone diseases non-invasively, with Raman spectroscopy. SORS is a non-invasive, high-throughput, robust analysis technique with vast potential for clinical use in vivo. Alongside the clinical study, specimens have been collected, following consent, from patients with osteoarthritis undergoing total knee replacements. The results supported our hypothesis: that changes in bone matrix chemistry, related to OA, can be detected in the subchondral bone prior to overt cartilage damage by Raman spectroscopy. Furthermore, for the first time we demonstrated that there is no difference in matrix chemistry between the medial and lateral compartments of the knee joint, within each cohort. However there is a large overall degree of separation (confidence interval = 0.95) between the non-OA and OA specimens. But there are also significant differences between the spectral signatures of OA and non-OA sample cohorts. Our data provide support that chemical changes in bone are associated with the initiation of, or predisposition toward, joint degeneration. The results demonstrate that Raman spectroscopy should be further developed as a future tool to provide screening for early detection of joint degeneration based on correlating molecular-specific modifications in the subchondral bone. The following links relate to dissemination of our work to interested parties and the general public. http://www.rnoh.nhs.uk/sites/default/files/downloads/12-156_rnoh_a4_20_articulate_autumn_2012_web_release.pdf http://www.rnoh.nhs.uk/sites/default/files/downloads/12-222_rnoh_articulate_winter_2013_web_release.pdf http://www.brittlebone.org/raman-spectroscopy.html?searched=raman&advsearch=oneword&highlight=ajaxSearch_highlight+ajaxSearch_highlight1
Our other studies looking at OI and OP also supported our hypothesis that Raman can detect bone disorders non-invasively, going beyond existing X-ray and associated methods because of its ability to identify chemical specific changes in BOTH mineral and organic bone components.
The project terminated in 2015, however we have been unable to secure follow on funding to optimise the clinical prototype for appropriate use in a hospital setting. HOWEVER, despite much frustration the team have furthered the work in terms of identifying the specific practical details, including SORS instrument requirements to obtain the quality of data required. In short the need is to implement an improved signal to noise ratio of c. 3 times which can be readily achieved using a "next generation instrument complying with Class 1C laser safety code. Finally, the last post-doc associated with the project was able to develop an advanced software using multivariate analysis and adaptive AI machine learning type algorithm (Churchwell et al. J. Raman Spectroscopy Volume: 51, 66-78, 2020).
Exploitation Route The application of SORS to measure both the organic and mineral phases of the bone transcutaneously in vivo has been achieved for the first time and the promised milestone achieved. The study paves the way for more accurate, safe and cost-effective way of exploring and monitoring bone disease to meet the needs of the modern health service to enable both patients suffering from, or at risk of bone disease to be treated. There is now realistic potential to utilise and translate our data in the development of devices for screening, diagnosis and monitoring of treatment in a range of genetic and degenerative bone conditions. We believed that we had cleared the way for the UK to lead this highly topical area of research for both health and economic benefits. Unfortunately 3 applications failed with reviewers being critical of the iterative and incremental nature of the next stage enabling clinical capability. Whilst we understand the nature of these comments we have been unable to obtain practical advice on how to proceed and enable UK PLC to reap the rewards of the investment to date.



We also anticipate the data will contribute to the understanding of the mechanicsms that control the matrix chemistry of bone as a material in relation to bone as a structure. This could identify therapeutic targets for novel approaches in treating conditions relating to abnormalities in bone matrix composition.
Sectors Healthcare,Leisure Activities, including Sports, Recreation and Tourism,Pharmaceuticals and Medical Biotechnology

 
Description The concept of assessing bone health, comprehensively, has been advanced and the involvement of public stakeholder dissemination enhances understanding and awareness of the importance of bone health in relation to degenerative conditions associated with an ageing population. Also the need to identify "at risk" individuals at an early stage prior to clinical symptoms to enable lifestyle changes that enhance healthy independent living in the aged. The validation of concept justifies ongoing development to attain a stage from which the commercial potential can be unlocked for UK plc. There remains huge potential to develop the concepts at the highest international level to fight bone disease.
First Year Of Impact 2010
Sector Healthcare
Impact Types Societal,Economic

 
Description UCL grant IAA project Secondment of John Churchwell to Central Laser Facility Rutherford Appleton Laboratory 
Organisation Rutherford Appleton Laboratory
Department Central Laser Facility
Country United Kingdom 
Sector Academic/University 
PI Contribution Award of an IAA grant from the UCL allocation, EP/K503745/1, enabled the PDRA John Churchwell to be seconded to RAL for six month to develop novel data processing and analtyical tools for the RAMAN bone spectra from the SORS sysem. This was to progress the translational potential of the system toward a rapid screening and auto diagnosis of bone health and disease.
Collaborator Contribution The team worked clodely together to support the PDRA in this secondment.
Impact 1. IP for analytical routines - being processed by UCLBusiness in co-operation with STFC 2. Submission of a paper on the routines withheld pending IP protection.
Start Year 2016
 
Description 114. Lasers for Spectroscopy and Imaging - developing new forms of cancer treatment and diagnosis of bone disease. Seminar, University of Southampton, 15 May 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact University seminar - provided background for discussing research and future EPSRC applications in relation to understanding properties of bone towards development of understand disease and healthy tissue.
Year(s) Of Engagement Activity 2013
 
Description 115. Raman Spectroscopy of Bone and the Invention of Spatially Offset Raman Spectroscopy Taiwan Association of Raman Spectroscopy, Summer Camp - Taiwan, June 2014 Invited 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact This was a summer camp over 4 days whereby international experts were invited to give lectures on research to encourage young people into science.
Year(s) Of Engagement Activity 2014
 
Description Archaeology: Rickety old ship 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Started an online discussion

the public commented on the study.
Year(s) Of Engagement Activity 2014
URL http://www.economist.com/news/science-and-technology/21636696-laser-based-tests-might-diagnose-bone-...
 
Description BBC South TV News Can Mary Rose remains help modern medicine? 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact TBC
Year(s) Of Engagement Activity 2014
 
Description Can Mary Rose remains help modern medicine? BBC Breakfast broadcast 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Informed the public about our research and led to further coverage.

We were subsequently contacted by other BBC departments wanting to broadcast the information.
Year(s) Of Engagement Activity 2014
 
Description Can Mary Rose remains help modern medicine? BBC news 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Not yet reported
Year(s) Of Engagement Activity 2014
URL http://www.bbc.co.uk/news/uk-30491175
 
Description How Mary Rose sailors could help fight Rickets: Daily Telegraph 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Not yet known
Year(s) Of Engagement Activity 2014
 
Description Laser Technology Reveals Rickets in Mary Rose Sailors 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Not yet known
Year(s) Of Engagement Activity 2014
URL http://www.archaeology.org/news/2834-141217-mary-rose-bones
 
Description Laser techniques used on bones of Mary Rose crew could detect modern 'Tudor-era' diseases 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Not yet known
Year(s) Of Engagement Activity 2014
URL http://www.culture24.org.uk/history-and-heritage/archaeology/art510218-Laser-techniques-used-on-bone...
 
Description Laser technology hope for bone illness sufferers Wantage & Grove Herald 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Not yet known
Year(s) Of Engagement Activity 2014
 
Description Laser technology hope for bone illness sufferers: Abingdon Herald 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Not yet known
Year(s) Of Engagement Activity 2014
 
Description Laser technology hope for bone illness sufferers: Didcot Herald 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Not yet known
Year(s) Of Engagement Activity 2014
 
Description Laser technology hope for bone illness sufferers: Wallingford Herald 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Not yet known
Year(s) Of Engagement Activity 2014
 
Description Lasers see us in a different light 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Royal National Orthopaedic Hospital magazine. Increased interest and participation

increased recruitment
Year(s) Of Engagement Activity 2012
 
Description Maritime Executive 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact not yet known
Year(s) Of Engagement Activity 2014
URL http://www.maritime-executive.com/article/New-Laser-Technology-Investigates-Sailors-Bones
 
Description Mary Rose Study, BBC Wales Broadcast 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Not yet known
Year(s) Of Engagement Activity 2014
 
Description Mary Rose Study: BBC World Service 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Not yet known
Year(s) Of Engagement Activity 2014
 
Description Mary Rose sailors had childhood rickets, study finds. BBC online 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Further discussion with collaborators.

TBC
Year(s) Of Engagement Activity 2014
URL http://www.bbc.co.uk/news/uk-england-hampshire-30486774
 
Description Mary Rose's crew was riddled with rickets: Lasers reveal damage to sailors' bones who perished on Henry VIII's ship: Daily mail 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Spotted by other media interest.

Not yet reported
Year(s) Of Engagement Activity 2014
URL http://www.dailymail.co.uk/sciencetech/article-2875880/Mary-Rose-s-crew-riddled-rickets-Lasers-revea...
 
Description Newspaper Blog - How the Crew of the Mary Rose are Protecting the Children of Today 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Press relaease attacted interest and the project used as example of how archaelogical aspects of research can inform understanding of modern diseases.

Enhanced breadth of interest in the project
Year(s) Of Engagement Activity 2015
URL http://www.huffingtonpost.co.uk/simon-m-clabby/mary-rose_b_6522522.html
 
Description Newspaper article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact This article stimualted public interest and enquiries.

May have stimulated interest in participation
Year(s) Of Engagement Activity 2014
URL http://www.express.co.uk/news/health/470032/A-new-laser-scan-can-spot-arthritis-before-the-symptoms-...
 
Description Raman Spectroscopy - A Crash Course, University of Stellenbosch Summer Student Workshop December 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Gave a introductory presentation on Raman spectroscopy with particular reference to medicine and biological applications. This was very a "teaching" lecture to introduce students to the subject.
Year(s) Of Engagement Activity 2015
 
Description Raman4Clinics Summer School Coimbra Portugal, 7 - 12 October 2018. Under COST Programme - Plenary Lecture - "Spatially Offset Raman Spectroscopy: Seeing Bone Disease In New Light" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Raman4Clinics pools European expertise to step forward in the field of novel, label-free and rapid technologies based on a wide variety of Raman spectroscopies for the clinical diagnostics of body fluids, bacteria, cells and tissues. International interdisciplinary networking opportunities are offered between scientists within biophotonics, chemometricians and physicians/clinicians. All participating research group are united in pursuing the goal of giving a major impetus in this vibrant field of research by aligning it to clinical requirements and application aspects (the unmet medical need) by means of COST as the best mechanism to progress the state-of-the-art. The Action creates a platform for scientific communication, exchange, collaboration and for new research activities, combining the partners' expertise in technology, component, system and methodology development and medical application. As a result, novel technology portfolios for clinical diagnostics will emerge to the benefit of patients as well as to the economy. 40 post grad students & 10 academics/industrialists.
Made new collaborations and potential new projects.
Year(s) Of Engagement Activity 2018
URL https://www.raman4clinics.eu
 
Description Royal National Orthopaedic Hospital web site research announcement 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Update on research project and providing information for new participants.

Enquiries re participating
Year(s) Of Engagement Activity 2014
URL https://www.rnoh.nhs.uk/home/news/raman-study-100th-participant-completed
 
Description Royal National Orthopaedic Hospital web site research announcement 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Update on research project and providing information for new participants.

Enquiries re participating
Year(s) Of Engagement Activity 2014
URL https://www.rnoh.nhs.uk/home/news/raman-study-100th-participant-completed
 
Description Spatially Offset Raman Spectroscopy For Transcutaneous Detection of Bone Disease. African Laser Center Workshop, Cape Town 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact General lecture on technology and application of SORS to South African and African continent post-graduate students - attended by c. 100 students in all branches of applications of lasers.
Year(s) Of Engagement Activity 2015
 
Description Strategies for life long musculoskeletal health - is exercise good for you? 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Ealing and District - University of the Third Age

Public Engagement in Science.

Interest in project and interest in the clinical study.
Year(s) Of Engagement Activity 2012
 
Description Study identifies prevalence of rickets among 16th century sailors 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Not yet known
Year(s) Of Engagement Activity 2014
URL http://www.heritagedaily.com/2014/12/study-identifies-prevalence-rickets-among-16th-century-sailors/...
 
Description Study identifies prevalence of rickets among 16th century sailors 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Not yet known
Year(s) Of Engagement Activity 2014
URL http://phys.org/news/2014-12-prevalence-rickets-16th-century-sailors.html
 
Description Tissue Imaging & Spectroscopy. African Laser Centre Summer School November 2018, Stellenbosch, South Africa Invited Plenary Lecture University Of Stellenbosch, South Africa. Workshop - "Spatially Offset Raman Spectroscopy: Seeing Bone Disease In New Light" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact To discuss and educate methods (mainly laser/optical based) for analysing tissue in relation to disease diagnosis.
The African Laser Centre (ALC) was established on 6 November 2003 at a meeting of the African Ministerial Council on Science and Technology (AMCOST) in Johannesburg. The objective of the ALC is to foster laser science in Africa by encouraging laser science and optics-related research collaboration between African researchers and institutions.
The meeting I attended is an event bringing together laser researchers (students to senior academics and political funding and educational organisations. It covers the whole breadth of laser applications in the African continent and attended by 100 students and researchers. The National Laser Centre of South Africa is also present.
Over the past decade, the ALC has awarded 18 postgraduate scholarships, of which five were for MSc and 13 for PhD candidates.
The activity also relates to Newton project funding between Central Laser Facility, STFC and Dept of Physics Univ of Stellenbosch. Not on Research Fish
Year(s) Of Engagement Activity 2018
URL http://www.laser-research.co.za/sarchi/Site/Home.html
 
Description magazine article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Gneral public interest in science

Indirect influence on understanding science and appreciation of new ideas that may impact on disease managment
Year(s) Of Engagement Activity 2014
URL http://arthritisdigest.co.uk/pioneering-technique-may-enable-early-diagnosis-of-osteoarthritis/