Mass Spectrometry Imaging of Biological Tissue
Submitting InstitutionSheffield Hallam University
Unit of AssessmentBiological Sciences
Summary Impact TypeTechnological
Research Subject Area(s)
Physical Sciences: Other Physical Sciences
Chemical Sciences: Analytical Chemistry
Biological Sciences: Biochemistry and Cell Biology
Summary of the impact
Clench's research on Matrix Assisted Laser
Desorption Ionisation - Mass Spectrometry
Imaging (MALDI-MSI) technologies has impacted directly
on pharmaceutical industry practice regarding studies of drug distribution
studies in biological tissues, providing increased information, more
rapidly. Companies have benefitted from long-term relationships with Clench's
Bioanalysis Research Group and seek its expertise for consultancy purposes.
Former members of Clench's group hold key positions in industry,
implementing and further developing these technologies. Francese has
had significant success in applying MALDI-MSI to analysis of latent
fingermarks for forensic applications benefiting Home Office scientists and
crime scene investigation units. Research advances in MALDI-MSI by Clench
and Francese are patented and exploited via licensing.
Clench has a track record of research at Sheffield Hallam
University (SHU) (1993-current) in novel applications of mass
spectrometry, working with global pharmaceutical companies, to advance
techniques applied to distribution of drugs and their metabolic
derivatives in biological tissues. Further collaborations in MALDI-MSI,
led by Clench with colleagues at Bradford, York and Sheffield
universities, resulted in highly cited publications.
Clench's initial research, as a senior lecturer at SHU, was funded
by Pfizer Global R&D 1999 -2003 (grant 1) to investigate methods of
adapting MALDI-MSI to study the distribution of pharmaceuticals in
biological tissues. In 2004, Clench's group published the first
European paper on MALDI-MSI of pharmaceuticals in Europe and only the
second in the world. Co-authored with a Pfizer scientist, this publication
(reference 1) detailed a method for studying the distribution of an
anti-fungal compound in skin. Further work with Syngenta (Bracknell, UK)
identified agrochemicals in plants and led to the application of MALDI-MSI
in the horticultural sector (reference 2). Distribution of the
bioreductive drug AQ4N and its active metabolite in solid tumours was
reported in 2007 in association with researchers at the Institute of
Cancer Therapeutics, University of Bradford (reference 3).
Clench received funding from the Engineering and Physical Sciences
Research Council (EPSRC) with the Royal Society of Chemistry to support
two Analytical Science CASE studentships in collaboration with Applied
Biosystems/MDS Sciex, manufacturers of mass spectrometers, to develop
instrumentation for MALDI-MSI and to expand the range of applications
(grant 2). High repetition lasers and aspects of sample preparation for
small molecules were investigated. One key development was the adaptation
of a commercial QqTOF mass spectrometer to incorporate a 20kHz Nd:YVO4laser;
it provided a novel patented method for homogenising the laser beam
(Patent GB2460478B, EP2297770B) resulting in higher quality images
(reference 4). Clench improved the specificity of MALDI-MSI
analysis for small molecules and proteins in collaboration with Syngenta
and GlaxoSmithKline (GSK) (grants 3, 4). This research enhanced the
technique by incorporation of ion-mobility separation (IMS) in conjunction
with MALDI-MSI to give increased specificity in images generated by ions
of the same m/z, based on separation by conformation (reference
5). Clench has an on-going collaboration with Waters Corporation
in co-development of instrumentation and software for Matrix Assisted
Laser Desorption Ionisation Ion Mobility Separation Mass Spectrometry
In 2008, Clench was invited by Cancer Research UK, together with
Professors Tozer and Paley at the University of Sheffield, to submit an
application, which was subsequently funded (£200,654, amount received by
SHU) to investigate protein signatures in tumours following
vascular-targeted therapies (grant 5). This led to 5 high impact papers
including reference 5. Funding was also obtained from the European
Cosmetic Agency (grant 6) to use MALDI-MSI to analyse ex vivo
human skin for the identification of irritants and sensitisers.
Francese, who joined SHU in 2008 in her first lectureship post,
collaborated with Clench on a number of aspects of MALDI-MSI
including the adaptation of the laser in mass spectrometers to improve
image visualisation (reference 4). Francese then went on to adapt
the technique of MALDI-MSI for examination of latent fingermarks, which
combined identification of an individual with information on the chemical
content of fingermarks (reference 6). This research led to two patented
technologies (GB2489215B and GB2493998A, in the UK and pending
international applications WO2012120279 and WO2013027011). Eleven peer
reviewed papers on the developments of this technique for fingermark
analysis have been published and funding from the Home Office (grant 9)
obtained to determine the feasibility of incorporating MALDI-MSI into
routine fingermark analysis.
Grants 7, 8 and 10 demonstrate GSK's continued support and interest in
MALDI-MSI research in the Bioanalysis research group at SHU.
References to the research
1. Bunch J, Clench MR, Richards DS (2004) Determination of
pharmaceutical compounds in skin by imaging matrix-assisted laser
desorption/ionisation mass spectrometry.
Rapid Communications in Mass Spectrometry, 18, 3051-3060. (66
citations). DOI: 10.1002/rcm.1725
2. Mullen AK, Clench MR, Crosland S, Sharples KR (2005)
Determination of agrochemical compounds in soya plants by imaging
matrix-assisted laser desorption/ionisation mass spectrometry. Rapid
Communications in Mass Spectrometry, 19, 2507-2516. (28 citations).
3. Atkinson SJ, Loadman PM , Sutton C, Patterson, LH, Clench
MR (2007) Examination of the distribution of the bioreductive drug
AQ4N and its active metabolite AQ4 in solid tumours by imaging
matrix-assisted laser desorption/ionisation mass spectrometry. Rapid
Communications in Mass Spectrometry, 21, 1271-1276. (44 citations).
4. Trim PJ, Djidja MC, Atkinson SJ, Oakes K , Cole LM, Anderson
DMG, Hart PJ, Francese S, Clench MR (2010). Introduction
of a 20 kHz Nd:YVO4 laser into a hybrid quadrupole time-of-flight mass
spectrometer for MALDI-MS imaging. Analytical and Bioanalytical Chemistry,
397, 3409-3419. (21 citations). DOI: 10.1007/s00216-010-3874-6.
5. Cole LM, Djidja M-C, Bluff J, Claude E, Carolan VA, Paley M,
Tozer GM, Clench MR (2011) Investigation of protein induction in
tumour vascular targeted strategies by MALDI MSI. Methods, 54 (4), 442-453
(10 citations). DOI: 10.1016/j.ymeth.2011.03.007. Clench,
REF 2, Output 2.
6. Wolstenholme R, Bradshaw R, Clench MR, Francese
S. (2009). Study of latent fingermarks by matrix-assisted laser
desorption/ionisation mass spectrometry imaging of endogenous lipids.
Rapid Communications in Mass Spectrometry, 23 (19), 3031-3039. (34
DOI: 10.1002/rcm.4218. Francese REF 2 output 4.
Key grants awarded to Clench for MALDI-MSI
1. 1999-2003 - Pfizer Global R&D (£52,770). Application of
MALDI/MS to the analysis of small molecules in biological tissues.
2. 2004-2008 - EPSRC/RSC Two Analytical Science CASE Studentships
in collaboration with Applied Biosystems/MDS Sciex (£114,000). Imaging
Matrix Assisted Laser Desorption Ionisation Mass Spectrometry.
3. 2005-2008 - BBSRC CASE Award Syngenta (£56,600). Imaging
MALDI-MS for the Examination of The Uptake and Distribution of Xenobiotics
4. 2006-2009 - BBSRC CASE Studentship GSK S3093 (£61,500). Imaging
MALDI-MS for Direct Drug Distribution Analysis.
5. 2008-2013 - Cancer Research UK (£200,654K). Magnetic resonance
and matrix assisted laser desorption mass spectrometry imaging for
progressing the development of tumour vascular targeted drugs.
6. 2008-2012 - COLIPA European Cosmetic Association (£253,041K).
Using human skin models to assess for chemical sensitivities using a
combined tissue imaging mass spectrometry approach together with
7. 2009-2012 - MRC Case studentship with GSK (STU029065)
(£79,300). The application of MALDI Mass spectrometry and related
techniques for imaging drug disposition in asthma, COPD and other
respiratory disease models.
8. 2011 - 2014 - Steifel (GSK) STU/10024881 (£78,500K).
Examination of pharmacotoxicological dynamic responses by mass
spectrometry imaging and profiling.
Key Grants awarded to Francese for MALDI-MSI
9. 2011-2014 - Home Office Ref: HOS/11/017 (£38,250). Integration
of MALDI MSI in to the Home Office operational fingermark examination
10. 2012-2016 - BBSRC Case studentship with GSK (BBSRC
BB/K501104/1) (£124,173). Using ion mobility mass spectrometry to
investigate the distribution and effect of dosed compounds on endogenous
Details of the impact
Clench and Francese's research on mass spectrometry
imaging has impacted upon the pharmaceutical industry specifically with
GSK collaborators (source 1), whilst training of staff from Unilever by Clench's
group at Sheffield Hallam University has facilitated knowledge transfer of
the technique into industry. Four technologies have been patented with
regards to mass spectrometry techniques and applications, in the UK, EU,
USA and China, two of which are licensed to commercial partners,
Elforlight Ltd (source 2) and Consolite Forensics. Technique development
work by the Bioanalysis group has changed practice within the
pharmaceutical industry. Specifically, a sustained professional
relationship with GSK since 2006, with a succession of CASE studentships
(4), has enabled the group to influence the methodology used to assess
drug distribution in animal models. By allowing faster tracking of
label-free drugs with higher spatial resolution than previously obtained,
this collaborative work has speeded up the drug discovery pipeline. More
recent work by Francese with the Home Office to embed MALDI mass
spectrometry analysis of fingerprints into routine forensics is gaining
impact. Francese is working with West Yorkshire Police to provide
information on fingerprint and non fingerprint forensic evidence, which is
feeding into their crime scene investigations. The technology developed by
Francese is reported in the new 2014 manual of fingerprint
development techniques, edited by the Home Office, as one of the
technologies with strong potential to be adopted by practitioners.
Comments from (source 3) confirms the impact of the technique in forensic
`The impact that the MALDI-MSI research can have in fingerprint and
forensic science include increased detections, adding contextual
evidence to cases and providing higher specificity in substance
identification than existing processes'.
`MALDI-MSI offers significant potential to enhance contextual
information that can be obtained from fingermarks, in particular the
presence and location of contaminants of operational interest that may
be present in marks. It offers other potential operational benefits such
as revealing additional ridge detail that has not been detected by other
chemical/physical techniques, and the separation of overlapping marks
from different donors'
`Recent work to confirm that marks have been deposited in human blood
also offers an improvement in specificity over existing methods, which
only determine whether proteins or haem is present. This new method may
add confidence to conclusions drawn and overcome arguments often raised
about substances that may give `false positives' with existing
The primary paper (reference 1) reporting findings from the initial
project on MALDI-MSI of small molecules in collaboration with Pfizer
Global R&D, led to the adoption of the technique by pharmaceutical
companies following personal interaction of Clench with scientists
from companies including GSK, Syngenta, Quotient Bioresearch Ltd and
instrument manufacturers Waters Corporation (Source 4). Clench has
collaborated with Waters Corporation since 2006 and the company has
invested ~£350K p.a. in MALDI Imaging since then. A senior manager at
Waters Corporation (Source 4) commented that the company sells 5-10
million pounds worth of MALDI systems per annum of which 30% are for MALDI
imaging. He also commented 'in the early days (of mass
spectrometry imaging) your help was vital in getting us off the ground').
Specifically in the UK, GSK introduced the MALDI-MSI instrumentation at
its Stevenage site (source 1). Clench's investigations of
agrochemical distribution in plants using MALDI-MSI resulted in him
participating in a BBC programme "Afterlife - The Strange Science of
Decay", assessing N13 uptake of decayed plant material in
new plant growth by MALDI-MSI. The programme, which was broadcast by BBC4
on 06/12/2011 and repeated on 06/08/2012, attracted viewing figures of
613,000 and 234,000 respectively (source 7). Clench's research on
the combination of ion mobility separation with MALDI-MSI has been carried
out in collaboration with Waters Corporation, Manchester, one of the
world's leading instrument manufacturers. This significant collaboration
started in 2006 and is on-going; Waters Corporation sponsored the
Discovery & Life Science Webinar Series 2013(04/09/2013) in which Clench
discussed progress in MALDI-MSI of biological tissue and Francese
discussed multi-informative analysis of latent fingermarks by MALDI-MSI
(300 participants) (source 6). Clench's work was, and is, a major
contributory factor in Waters Corporation's decision to invest in
development of MALDI-IMS-MSI (source 4).
Francese's research on fingermark analysis attracted significant
media attention (sources 8 and 9). Since her initial paper in 2009, Francese
further developed the methodology to aid in the identification of sexual
assault victims and to analyse fingermarks recovered from crime scenes by
standard forensic techniques. She is funded by the Home Office (2011-2014)
(grant 9) to convert this research into a validated method (source 2). Francese
co-developed a powder discharge device (patent pending PCT/GB2013/051838)
(with Reed, SHU), which has been licensed to Consolite Forensics for
further development, to enhance the company's sales in the forensics
market. The initial work was funded through the EPSRC Bridging the Gap
award to SHU. Francese was featured on: The One Show, BBC1,
24/04/2012 (viewing figures 4,170,000), Fingerprint item; Science in
Action, BBC Radio World Service, 26/01/2012,
http://www.bbc.co.uk/programmes/p00n0f3d; and covered in national,
local and specialist press, including The Daily Mail, Yorkshire Post,
Science Daily, Police Oracle and The Engineer.
Clench and Francese provide expert advice and consultancy
to industry through the Unit's analytical services commercial group for
MALDI-MSI, including: Unilever R & D (£21K), Procter and Gamble
(£15K), Croda Chemicals (£43K), and Alk-Albello (Denmark) (£19K), (income
2008 - 10/2013). The scale of external impact of the MALDI-MSI work at SHU
was evidenced by three Mass Spectrometry open days held on: 29/07/2009, 35
Delegates (10 Industry, 21 Universities, 4 Other, which includes NHS,
Government laboratory staff); 14/07/2011, 111 Delegates (44 Industry, 53
Universities, 14 Other), 10/04/2013, 107 Delegates: 42 Industry, 60
Universities, 5 Other. The last of these open days was organised in
conjunction with the British Mass Spectrometry Society (source 5).
Two scientists trained in MALDI-MSI by Clench at SHU are now
exploiting this expertise, one at Novartis, Basel, Switzerland and a
second at instrument manufacturer Shimadzu, Manchester, UK, the latter as
the Global MALDI Applications Specialist. Clench's first PhD
student at SHU (completed in 2005) in MALDI-MSI was appointed as Head of
MALDI-MSI at the National Physical Laboratory in 2013.
In 2007/8 Clench was appointed as the British Mass Spectrometry
Society (BMSS) Lecturer in recognition of his research expertise in
MALDI-MS; he currently leads the Imaging Group within the BMSS. The award
enabled Clench to share his expertise through a lecture series in
the UK on MALDI-MSI. Francese shared her expertise in MALDI-MSI with
attendees at the International Symposium on Pharmaceutical and Biomedical
Analysis in Bologna, Italy in 2013 (source 10). Further demonstrating the
impact and importance of Clench's expertise, and the interest in
the technique by the healthcare community in the EU, he was appointed UK
member of the Management Committee of EU COST Action BM1104 "Mass
Spectrometry Imaging: New Tools for Healthcare Research"
Sources to corroborate the impact
Source 1. Principal Research Analyst, GlaxoSmithKline, Stevenage
Source 2. Technical Director, Elforlight Ltd, Daventry
Source 3. Research Scientist, Home Office Centre for Applied
Science and Technology, St Albans
Source 4. Senior Manager, Waters Corporation, Manchester
Source 5. Chairman British Mass Spectrometry Society and Associate
Principal Scientist, AstraZeneca, Macclesfield
Source 6. Biocompare Webinar, sponsored by Waters Corporation
4/9/2013: Clench and Francese https://waters.omnovia.com/registration/52751363643813
300 participants signed up for live event).
Source 7. "After Life: The Science of Decay" http://www.bbc.co.uk/programmes/b012w66t
Source 8. "Fingerprint breakthrough offers new forensic evidence"
Source 9."Pioneering Fingermark Technology Uses Mass Spectrometry
Imaging to Provide Crime Scene Investigators With Key Extra Details"
Source 10. Speaker profile and abstract for Francese from
International Symposium on Pharmaceutical and Biomedical Analysis, 2013. http://www.pba2013.org/speakers.html