Light-Activated Antimicrobial Polymers For Healthcare Applications

310 Pages·2015·29.11 MB·English

Light-Activated Antimicrobial
Polymers For Healthcare Applications
This thesis is submitted in partial fulfilment of the requirements for the Degree of Doctor
of Engineering (Chemistry)
sacha m noimark
.
2015
Supervised by: Professor Ivan P. Parkin, Dr Elaine Allan and Professor
Christopher W. M. Kay
DECLARATION
I, Sacha Noimark confirm that the work presented in this thesis is
my own. Where information has been derived from other sources, I
confirm that this has been indicated in the thesis.
ABSTRACT
This thesis details the development of potent light-activated antimi-
crobial silicone polymers for use in healthcare environments. Upon
illumination, these polymers induce the lethal photosensitisation of
bacteria through the generation of a range of reactive oxygen species
at the polymer surface, initiating a non-site specific attack against
bacteria in the vicinity. Activation of the antimicrobial technology
635
developed was achieved using laser illumination ( nm) and
UVA illumination for medical device applications, or white hospital
lighting conditions for hospital touch surface applications. Moreover,
for the first time, some photobactericidal materials developed also
demonstrated strong antimicrobial activity through an additional
dark-activated mechanism.
Antimicrobial polymers were developed through use of a swell-
encapsulation-shrink strategy to incorporate photosensitiser dyes
such as methylene blue and crystal violet, in addition to a range
2
of nanoparticles including nm gold nanoparticles, zinc oxide
nanoparticles and titania nanoparticles, into medical grade silicone.
Specifically, the photobactericidal silicone polymer systems detailed
2
in this thesis are: (i) crystal violet-coated, methylene blue and nm
gold nanoparticle-encapsulated silicone for both medical device and
hospital touch surface applications, (ii) crystal violet-coated, zinc
oxide nanoparticle-encapsulated silicone for hospital touch surface
applications and (iii) oleic acid-functionalised titania or gold-doped
titania nanoparticle-encapsulated silicone for medical device or
hospital touch surface applications (in combination with a suitable
light delivery system).
Thematerialswerecharacterisedusingtechniquesincluding:lightmi-
croscopy, fluorescence microscopy, transmission electron microscopy,
UV-Vis absorbance spectroscopy, X-ray photoelectron spectroscopy,
time-resolved electron paramagnetic resonance spectroscopy and
i
time-resolved detection of near infrared singlet oxygen phosphores-
∼ 1270
cence ( nm). Functional testing indicated that these materials
were suitable for targeted applications and demonstrated strong ma-
terial photostability and dye-polymer stability under aqueous con-
ditions. The polymers demonstrated strong light-activated antimi-
crobial activity when tested against key Gram-positive and Gram-
negative bacteria associated with hospital-acquired infections includ-
ingStaphylococcusaureus,StaphylococcusepidermidisandEscherichiacoli,
4
with > log reductions in viable bacterial numbers observed. Signifi-
cant antimicrobial activity was also noted under dark conditions. It is
anticipated that the potent antimicrobial technology detailed in this
thesis could ultimately be used in both medical device and hospi-
tal touch surface applications, to reduce bacterial surface colonisation
and the associated incidence of hospital-acquired infections.
ii
ACKNOWLEDGMENTS
Firstly, I would like to thank my primary supervisor, Professor Ivan
Parkin, for all his advice, support, encouragement and inspiration
over the years. I would also like to thank my secondary supervisor,
DrElaineAllan,forherhelpandinvaluableexpertiseinMicrobiology
and my tertiary supervisor, Professor Christopher Kay (UCL EPR),
for his EPR expertise, guidance and enthusiasm and for his patience
in teaching me how to use MATLAB! I would also like to take
this opportunity to thank Professor Michael Wilson, my secondary
supervisor in my first year of Doctoral Research, for introducing
me to the field of Microbiology and for providing me with a strong
foundation for future work in this area.
Over the course of my doctorate, I have had the opportunity to work
with many people covering a range of academic disciplines. First
and foremost, I would like to thank everyone on the ‘MRC Catheter
Project Team’. Without their diverse range of expertise, I could not
have achieved such an inter-disciplinary project. In particular, I
would like to thank Professor Sandy MacRobert, Dr Sandy Mosse, Dr
Melissa Bovis and Dr Josephine Woodhams at the National Medical
Laser Centre for their collaboration, excellent help and continual
support over the course of my research. My thanks also goes to
Dr Enrico Salvadori (UCL EPR) for his EPR expertise, spectrometer
tuning and MATLAB tutorials!
I would also like to thank all my colleagues at the Eastman Dental
Institute who have helped and supported me over the years. In
particular, I would like to thank Annapaula Correia who gave me a
crash course in microbiology, showed me countless useful tricks and
kept me company during countless hours of plating up bacteria!
UCL Chemistry has been an incredible and enjoyable environment to
work in, and in this friendly, collaborative atmosphere, my research
iii
has flourished. I would like to extend my thanks to the Parkin and
CarmaltgroupsandothercolleaguesatUCLChemistryfortheirhelp,
friendship and support. In particular I would like extend a massive
thank you to: Will (nanoparticle synthesis and TEM), Nuru (XPS), Joe
(nanoparticle functionalisation), Raul and Carlos (photocatalysis) for
all their technical expertise and advice in my project.
I would like to extend a special thank you to a close friend and
collaborator, Jonathan Weiner (Imperial College London). I still can’t
believe it, our crazy idea worked! Thank you for all your help over
the years, access to Imperial equipment - including the Titan(!) - and
for putting up with me and my countless emails whilst we wrote that
paper! I would also like to thank Matthew Allinson (Imperial College
London) for his help in running the ICP-OES experiments for us.
Thank you to all my friends, for being there for me throughout
and keeping me sane when work piled up! In particular, Jonathan
Hoyland, thank you so much for helping me format my thesis in
LATEX- I apologise for crazy code and disorganised labeling systems!
Last but by no means least, I would like to thank my Mum, Dad, Nan,
brothers and sister-in-laws for their love and support and for putting
up with me over the years! I would especially like to thank my Mum,
Gaby and Joel for being my ‘presentation practice crew’ - I honestly
don’t know how I would’ve got through them without you - and
my oldest brothers Dr Lee and Dr Dean for their profound patience,
despite my millions of questions, and for their help in explaining the
more medical aspects of my project.
iv
PUBLICATIONS
List of publications associated with this thesis:
1
[ ] S. Noimark, C. W. Dunnill and I. P. Parkin. Shining light on mate-
rials - a self-sterilising revolution, Advanced Drug Delivery Reviews,
65 570 580
2013, , - .
2
[ ] S. Noimark, M. Bovis, A. J. MacRobert, A. Correia, E. Allan, M.
Wilson and I. P. Parkin. Photobactericidal polymers; the incorpo-
ration of crystal violet and nanogold into medical grade silicone,
3 18383 18394
RSC Advances, 2013, , - .
3
[ ] S. Noimark, E. Allan and I. P. Parkin. Light-activated antimicro-
bial surfaces with enhanced efficacy induced by a dark-activated
5 2216 2223
mechanism, Chemical Science, 2014, , - .
4
[ ] S. Noimark, J. Weiner, N. Noor, E. Allan, C. K. Williams, M. S.
P. Shaffer and I. P. Parkin. Dual mechanism antimicrobial poly-
mer - ZnO nanoparticle and crystal violet encapsulated silicone,
25 1367 1373
Advanced Functional Materials, 2015, , - .
5
[ ] S. Noimark, K. Page, J. C. Bear, C. Sotelo-Vazquez, R. Quesada-
Cabrera, Y. Lu, E. Allan, J. A. Darr and I. P. Parkin. Functionalised
gold and titania nanoparticles and surfaces for use as antimicro-
175 273 287
bial coatings, Faraday Discussions, 2014, , - .
6
[ ] S. Noimark, E. Salvadori, R. Gomez-Bombarelli, A. J. MacRobert,
C. W. M. Kay and I. P. Parkin. Photoexcitation of phenothiazine
and triarylmethane photosensitiser dyes, 2015, (Manuscript in
Preparation).
v
CONTENTS
1 hospital acquired infections strategies to re
- ; -
duce catheter related infections 1
-
11 1
. Introductory Remarks . . . . . . . . . . . . . . . . . . . .
12 2
. An Introduction to Hospital-Acquired Infections . . . . .
121 3
. . The escalating burden of bacterial drug-resistance
122
. . Catheter-associated infections; the origins of an
4
acute problem . . . . . . . . . . . . . . . . . . . . .
13 7
. The Use of Antimicrobial Agents for Infection-Prevention
131 8
. . Antimicrobial lock therapy . . . . . . . . . . . . .
132 10
. . Ethanol lock therapy . . . . . . . . . . . . . . . . .
133 12
. . Antimicrobial flushes . . . . . . . . . . . . . . . . .
134 14
. . Evaluation of Antimicrobial Locks and Flushes .
14
. Antimicrobial Medical Devices as an Infection-
14
Prevention Strategy . . . . . . . . . . . . . . . . . . . . . .
141 15
. . Antiseptic wound-dressings . . . . . . . . . . . . .
142 19
. . Antimicrobial catheter cuffs . . . . . . . . . . . . .
143 20
. . Antibiotic-coated catheters . . . . . . . . . . . . .
144 24
. . Silver-coated anti-infective catheters . . . . . . . .
145
. . Chlorhexidine and silver sulfadiazine-coated
25
catheters . . . . . . . . . . . . . . . . . . . . . . . .
146 29
. . Oligon catheters . . . . . . . . . . . . . . . . . . . .
147 30
. . Silver/ hydrogel-coated catheters . . . . . . . . . .
148
. . Problems associated with the use of silver as an
32
infection-prevention strategy . . . . . . . . . . . .
149 33
. . Heparin-coated catheters . . . . . . . . . . . . . .
1410 35
. . Are anti-infective devices the way forward? . . .
2 photodisinfection of surfaces 64
21 64
. Photodynamic Therapy Approach . . . . . . . . . . . . .
211 64
. . Photodynamic Therapy; A Brief History . . . . . .
212 66
. . The Use of Photosensitiser Molecules in PDT . . .
22 71
. Self-Sterilising Polymers . . . . . . . . . . . . . . . . . . .
221
. . TheRoleofSurfacesinHospital-AcquiredInfec-
71
tion . . . . . . . . . . . . . . . . . . . . . . . . . . .
vi
222
. . Porphyrin-Based Light-Activated Antimicrobial
73
Polymers . . . . . . . . . . . . . . . . . . . . . . . .
223
. . Phenothiazine-Based Photobactericidal Poly-
74
mers to Coat Surfaces . . . . . . . . . . . . . . . .
224
. . Incorporation of Photosensitiser Dyes into Med-
76
ical Grade Polymers . . . . . . . . . . . . . . . . .
23 82
. Research Aims . . . . . . . . . . . . . . . . . . . . . . . . .
3 laser activated antimicrobial polymers
- ;
crystal violet methylene blue and gold
,
nanoparticle encapsulated silicone 98
-
31 98
. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .
32 102
. Experimental . . . . . . . . . . . . . . . . . . . . . . . . . .
321 102
. . Chemicals and Substrates . . . . . . . . . . . . . .
322 102
. . Materials Synthesis . . . . . . . . . . . . . . . . . .
323 104
. . Materials Characterisation . . . . . . . . . . . . . .
324 105
. . Functional Testing . . . . . . . . . . . . . . . . . .
325 106
. . Microbiological Investigation . . . . . . . . . . . .
33 110
. Results and Discussion . . . . . . . . . . . . . . . . . . . .
331 110
. . Materials Synthesis . . . . . . . . . . . . . . . . . .
332 113
. . Materials Characterisation . . . . . . . . . . . . .
333 122
. . Functional Testing . . . . . . . . . . . . . . . . . .
334 125
. . Microbiological Testing . . . . . . . . . . . . . . . .
34 132
. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . .
4 white light activated antimicrobial poly
- -
mers crystal violet methylene blue and gold
; ,
nanoparticle encapsulated silicone 140
-
41 140
. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .
42 143
. Experimental . . . . . . . . . . . . . . . . . . . . . . . . . .
421 143
. . Chemicals and Substrates . . . . . . . . . . . . . .
422 143
. . Synthesis of Gold Nanoparticles . . . . . . . . . .
423 143
. . Materials Synthesis . . . . . . . . . . . . . . . . . .
424 145
. . Materials Characterisation . . . . . . . . . . . . . .
425 145
. . Dye Adherence Testing . . . . . . . . . . . . . . . .
426 146
. . Sample Photostability Testing . . . . . . . . . . . .
427 146
. . Wetting Properties . . . . . . . . . . . . . . . . . .
428 146
. . Microbiological Testing . . . . . . . . . . . . . . . .
43 150
. Results and discussion . . . . . . . . . . . . . . . . . . . .
vii
431 150
. . Materials Synthesis and Characterisation . . . . .
432 154
. . Microscopy . . . . . . . . . . . . . . . . . . . . . . .
433 157
. . Functional Properties . . . . . . . . . . . . . . . . .
434 162
. . Bactericidal Properties . . . . . . . . . . . . . . . .
44 171
. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . .
5 white light activated antimicrobial polymers
- ;
crystal violet and zinc oxide nanoparticle
-
encapsulated silicone 180
51 180
. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .
52 183
. Experimental . . . . . . . . . . . . . . . . . . . . . . . . . .
521 183
. . Chemicals and Substrates . . . . . . . . . . . . . .
522 183
. . Materials Synthesis . . . . . . . . . . . . . . . . . .
523 184
. . Materials Characterisation . . . . . . . . . . . . . .
524 185
. . Functional Testing . . . . . . . . . . . . . . . . . .
525 186
. . Sample Photostability Testing . . . . . . . . . . . .
526 186
. . Microbiological Investigation . . . . . . . . . . . .
53 188
. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
531 188
. . Material Synthesis . . . . . . . . . . . . . . . . . .
532 189
. . Materials Characterisation . . . . . . . . . . . . . .
533 196
. . Functional Properties . . . . . . . . . . . . . . . . .
534 200
. . Microbiological Testing . . . . . . . . . . . . . . . .
54 206
. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . .
6 photoexcitation of phenothiazine and triaryl
-
methane photosensitiser dyes encapsulated in
medical grade silicone 214
61 214
. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .
62 217
. Experimental . . . . . . . . . . . . . . . . . . . . . . . . . .
621 217
. . Chemicals and Substrates . . . . . . . . . . . . . .
622 217
. . Materials Synthesis and Characterisation . . . . .
623 218
. . Photochemical Activity Investigations . . . . . . .
63 221
. Results and Discussion . . . . . . . . . . . . . . . . . . . .
631 221
. . Material Synthesis and Characterisation . . . . . .
632 224
. . Photosensitiser Dye-Encapsulated Silicone . . . .
633
. . Photosensitiser Dye and Gold Nanoparticle-
234
Encapsulated Silicone . . . . . . . . . . . . . . . .
64 237
. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . .
viii