![Plasmonic Sensors and their Applications, First Edition. Edited by Adil Denizli.
© 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.
1
1
1.1 Introduction
Recent advances in health technologies have remarkable impact on health-care system.
Advanced health technologies are however not affordable and available for resource-
constraint settings. From global health perspective, recent improvements in health tech-
nologies need to reflect alternative solutions for overcoming such inequalities by developing
new technologies and strategies in the manners of cost-effective, rapid, easy-to-use, and
portable size, hereby minimizing the disparities between resource-rich and limited settings
[1, 2]. In this regard, biosensing arena has enormous applications in diverse fields, span-
ning from biomedicine to agriculture; for instance, monitoring vital information for dis-
eases detection or determining the presence of contaminants in water and soil [2]. The
concentrations of analytes can be accurately determined based on a linear association
between signal intensity and analyte concentrations via an analytical biosensor. In the
field, four types of biosensors, such as optical (mostly plasmonic sensors), electrochemical,
piezoelectric, and magnetic biosensor, are mainly employed for analytical measurements
[3]. Optical biosensors (e.g. surface plasmon resonance (SPR), localized SPR (LSPR),
surface-enhanced Raman scattering (SERS), plasmon-enhanced fluorescence (PEF),
surface-enhanced infrared absorption spectroscopy (SEIAS), etc.) are some of the mostly
applied biosensors in health-care biomedicine [4, 5]. Especially, SPR-stemmed platforms
have been benefitted in a vast majority of bio-analytical analyses since this technique ena-
bles rapid observation of bio-analytes in specimens, at the same time provides high sensi-
tivity and selectivity in comparison to currently available instruments [2, 6]. These sensors
basically monitor minute alterations in spectral properties of the plasmon by acting as a
transducer of the sensing signal [5]. The sensing mechanism is constituted by recognizing
and capturing the target analytes through bioreceptor which are immobilized on the metal
surface. Then local refractive index increases due to capturing and SPR signals are shifted
[7]. Their plasmonic fashion can be designed by considering the material and plasmonic
features, like surface-based strategies that support SPP mode or nanoparticle-based
Esma Derin1,2
, Özgecan Erdem1
, and Fatih Inci1,2
1
UNAM-National Nanotechnology Research Center, Bilkent University, Ankara, Turkey
2
Institute of Materials Science and Nanotechnology, Bilkent University, Ankara, Turkey
Deciphering Plasmonic Modality to Address Challenges
in Disease Diagnostics](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-16-320.jpg)
![1 Deciphering Plasmonic Modality to Address Challenges in Disease Diagnostics
2
modality that employs localized surface plasmon resonance (LSPR). The intensity and peak
position of the SPR have been influenced by the size, shape, and composition of the nano-
structures and also the surrounding environment’s dielectric properties. [5].To touch upon the
fundamentals of plasmonic sensors, they are stemmed from surface plasmon polariton (SPPs)
or plasmonics, which are basically defined as the collective oscillations of free electrons at the
metal surface [8]. Plasmonics deal with the electromagnetic (EM) wave and free electron inter-
actions through excitation on conductors, such as metals, semimetals or semiconductors [9].
The excited electrons leads to collective oscillation with the close frequency to EM wave [9].
The history of SPP modality takes back more than a century, however, the improve-
ments in the field have not accelerated until notable leaps in the nanotechnology (e.g.
nanoscale fabrication techniques) to achieve appropriate sized structures for the further
discoveries [10]. For instance, importantly note here, Kretschmann and Otto are two
pioneers to create Surface Plasmon Resonance (SPR) through coupling strategies.
Afterwards, SPR-based sensor was leveraged by Liedberg et al. through the antibody and
antigen relations, which can be identified as a critical direction for biosensing platforms
[11]. Today, SPR has been considered as one of the most powerful biosensing platforms,
especially in analytical chemistry and medicine [7].
1.2
Surface Plasmon Polaritons
SP is the propagating light waves at the conductor surface via trapping due to interactions
with free electrons [12]. Per these interactions, collective oscillations with light waves
result in a resonance as a response of free electrons [12]. The formation of the SP is carried
out by the resonant interactions of surface charge oscillations and electromagnetic field of
light, and these interactions enhance the dominancy of SPs simultaneously [12]. The defi-
nition of the SPP can be simplified as an electromagnetic wave, and more specifically, it is
transverse magnetic (TM)-polarized optical surface wave that propagates directly along a
surface between dielectric and a metal surface (Figure 1.1a) [13, 14]. In addition, metal
surfaces have crucial charge density wave, which constitutes SPPs with the combination
with electromagnetic fields that are maximum at the interface on the contrast through
both media since they are decreased exponentially [14]. The amplitude of the SPP is influ-
enced inversely (exponential decay) with the distance of each medium from the interface
[13]. In addition to the metal surface, SPPs can be obtained from different metal struc-
tures, such as thin films, stripes, differently sized and shaped nanoparticles or differently
patterns (e.g. holes, slits, grooves, gaps, or corrugations, etc.) [14]. SPPs or plasmonics are
mostly utilized by the fields of medical diagnostics, biosensing, spectroscopy, nanopho-
tonic, imaging, or circuitry due to their substantial properties, including energy asymp-
totes in dispersion curves, resonances, field enhancement and localization, high surface
and bulk sensitivities, and subwavelength confinements [8, 14]. Another point is that
SPPs have subwavelength property and field confinement since their ability is over-
weighted to traditional optical elements (e.g. lenses, spatial light modulators) by consider-
ing ability to spatial field modulations at nanoscale [8]. Majorly, Maxwell equations
between interface of conductor (e.g. metals) and a dielectric layer are crucial for the inves-
tigation of physical properties of SPPs [15].](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-17-320.jpg)
![1.2 Surface Plasmon Polariton 3
The characteristics of the SP modes, which can be either localized SPs of individual par-
ticles or several propagating SPPs on flat and curved, single and multiple surfaces, are
determined by the topology of the metal surface. In addition, SPP modes of complex parti-
cle arrays and metal nanostructures are also determined. Based on this unique property of
the SPP-based waveguides, the bandwidth of information can be transported by plasmonic
waveguides through conventional (dielectric-based) photonics. The interest in plasmon-
based nanophotonics is increased substantially [16]. When the SPP interacts with the
metal, its energy dissipates. Free electron scattering in the metal, which is bounded with an
ideal dielectric, creates loss due to absorption via inter-band transitions at a short enough
wavelength [14]. For the SPP, this loss is fundamental. Operating wavelength selection can
be selected carefully to avoid absorption via inter-band transitions or advanced fabrication
techniques can decrease the free-electron scattering, and however, the both cannot be elim-
inated [14]. As aforementioned, surface of the metal interface has influence on the SPP,
and moreover, the roughness creates additional loss since SPPs are scattered into bulk
waves [14]. The main drawbacks of this loss are limiting practical applications of SPPs
when it is excessive [14].
1.2.1 Excitation of the SPP
The excitation of the surface plasmon is mostly related to the conservation of the energy and
momentum of photon in the incident light on a metal−dielectric interface. The excitation of
the SPPs requires the momentum and energy matching to the incident photon’s and plasmon
Detector
Detector
Angle
Wavelength
Extinction
Reflectance
Reflected light
Incident light
Electromagnetic field
Electrons cloud
Nanoparticle
Dielectric
Light
Evanescent wave
SPP
Dielectric
Surface plasmons on planar
thin film–dielectric interface
Surface plasmons on
nanoparticle–dielectric interface
plasmonic-active thin fim
Light
Prism
θ
(a)
(b)
Figure 1.1 (a) SPP propagation is illustrated through thin film with the surface charges at the
metal and dielectric interface with the excitation, and the spectra is obtained after surface plasmon
excitation. (b) SPP is generated through nanoparticle surface to achieve localized surface plasmon
resonance (LSPR), and the spectra is obtained after surface plasmon excitation. Source: Reprinted
with permission from Bhattarai et al. [19]. © MDPI.](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-18-320.jpg)
![1 Deciphering Plasmonic Modality to Address Challenges in Disease Diagnostics
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modes in order to obtain charge-coupled oscillations [17]. Special techniques are the primary
requirement for the excitation of three-dimensional light beams in order to employ phase-
matching [15]. The excitation of surface charges route can be explained by the presence of
metal and dielectric interfaces and incoming p-polarized wave, which is transverse mode of
the parallel electric field vector to the interface with an angle. The incident wave reaches the
interface and split into two waves that are propagated in different directions [18].
Effective plasmon generation is achieved with the optical coupling element integration
into the system. Prism, grating, and waveguide coupling methods (Figure 1.2) are the
widely used light coupling techniques in comparison to waveguide, photonic crystal, and
fiber-optic based coupling. These applications utilize attenuated total reflection (ATR),
light diffraction or evanescent wave coupling from waveguide modes [17].
1.3
Surface Plasmon Resonance (SPR)
SPR is an optical biosensor that relies on the refractive index change of sensor surface,
denoting label-free and in real-time detection [2, 20]. The plasmonics can be defined basi-
cally interaction of light with metals or metallic nanostructures; hence, this mechanism
combines photonics and electronics to measure optical properties, e.g. spectra and refrac-
tive index changes at the nanoscale [3]. The interests in SPR biosensors have been increased
enormously over the years [21]. The application of the SPR mostly focuses on clinical diag-
nostics, biological and pharmaceutical analysis, food quality and safety evaluation since it
enables to monitor molecular interactions and quantify biomarkers, such as proteins, DNA
or whole cells [22].
SPP or SP is the main requirement to induce SPR in the interface between the metal (e.g.
gold or silver) and dielectric materials based on light excitation [22]. The generation of SPP in
the form of EM wave occurs after the interactions of the incident light with metal since, col-
lective oscillation of the free electrons is induced by the photons in the conduction band [23].
(a) (b)
nprism > nL
(c)
(d) (e) (f)
θSP
θSP
θSP1
θSP2
Figure 1.2 The common configuration of SPP excitations is depicted. (a) Kretschmann configuration,
(b) two-layer Kretschmann configuration, (c) Otto configuration, (d) excitation with an SNOM probe,
(e) grating diffraction, and (f) diffraction on surface features. Source: Reprinted with permission
from Zayats et al. [24]. © 2005, Elsevier.](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-19-320.jpg)
![1.4 Localized Surface Plasmon Resonance (LPSR 5
SPPs can be only sustained by p-polarized electromagnetic or transverse magnetic wave at an
interface of metal and dielectric medium. The sign of the dielectric constant has to be oppo-
site for instance gold, silver, copper, or aluminum, which have negative real and positive
imaginary dielectric constants, and therefore, they can be used for the SPP generation [23].
These indicated metals have both pros and cons; for instance, the negative real dielectric
constant of silver is the largest, which creates higher sensitivity against to refractive index
(RI) changes. However, its chemical stability is lower due to easy oxidation in air. In contrast
to silver, RI sensitivity of gold is lower, yet it holds higher stability and chemical versatility,
and hence, the functionalization of the sensor surface can be carried out much easier.
1.4
Localized Surface Plasmon Resonance (LPSR)
Localized surface plasmon resonance (LSPR) is an optical phenomenon produced as a result
of interactions between the incoming light and surface electrons in a conduction band
through a light wave trapped in conductive nanoparticles smaller than the wavelength of
light. This phenomenon is reliant on the size, geometry, dielectric environment, composi-
tion, and particle–particle separation distance of the nanoparticles [25]. Since metal nano-
structures interact with a beam of light, some of the incoming photons are absorbed, and the
rest are scattered in different directions. When LSPR is stimulated, these absorptions and
scattering events increase greatly. In metal nanostructures, LSPR is most easily detected by
an optical spectroscopic method, and this measurement is usually based on the extinction or
scattering events [26]. The differences between SPR and LSPR are illustrated in Figure 1.3.
In addition to gold and silver, which are the most commonly used plasmonic materials,
the other metals, such as copper [27] and aluminum [28, 29] also exhibit plasmon reso-
nance features [30]. Mostly, the physical properties of metal particles change considerably
when the size of particles is around nanoscale, and also, smaller than the wavelength of
Wavelength (nm)
Particles
θ λ
Film
SPR LSPR
Ansorbance
Reflectivity
Angle (°)
450
60 70 80
65 75 500 550 600 650
Figure 1.3 The schematic represents the basic principle and the difference between SPR and
LSPR. Source: Reprinted with permission from Jatschka et al. [37]. © Elsevier.](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-20-320.jpg)
![1 Deciphering Plasmonic Modality to Address Challenges in Disease Diagnostics
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light used to illuminate them [31]. In recent years, biosensors based on LSPR (majorly
stemmed from metallic nanoparticles) have begun to draw attention for the label-free bio-
sensing approaches due to its easy and colorimetric sensing features, as well as portability
and its ability to interface with multiplexed devices [30, 31]. LSPR biosensors can also be
easily integrated into miniaturized devices for point-of-care (POC) applications in order to
save cost and reach the assay at different settings [32–34]. Integrating full-automation to
these sensors also helps minimizing inter-personal errors for the measurements. Such inte-
grations enable rapid acceleration for biosensor deployment into the health-care settings
by promoting wider POC applications, such as bedside diagnosis, personalized medicine,
and wearable devices [35]. Mostly, two main methods are used in LSPR biosensors: direct
and indirect strategies. The first strategy tracks the shifts in the LSPR absorption peak due
to the refractive index changes upon binding of the target molecule. This direct analysis
requires less time and cost, but it has a limited sensitivity. The latter strategy is reliant on a
sandwich analysis, where LSPR is used to stimulate the labels. As the light is on, metal
nanostructures produce LSPR and are used to capture light near the surfaces [36].
On the other hand, there are also some obstacles. Since LSPR-based strategies are mostly
dependent on the changes in the refractive index at the close vicinity of nanoparticles, a
large number of molecules need to be localized around the particles in order to create a
plasmonic shift. Strategies, such as adjusting the size and shape of the nanoparticle mate-
rial, could be utilized to overcome this limit [30]. Another obstacle could be the reproduc-
ibility of sensor surface comprised of nanoparticles, ultimately limiting their utility and
expansion to hurdle the real-world problems in clinical use.
From an application perspective, sensitive and selective detection of cancer biomarkers is of
great importance in the early diagnosis of this disease. In a study, for instance, a LSPR lab-on-
a-chip was designed to detect human alpha fetoprotein and prostate-specific antigen, which
are cancer markers [38]. The microfluidic chip, which was developed by combining plas-
monic, microfluidics, nanofabrication, and surface chemistry, accommodated 32 detection
areas distributed across 8 independent microfluidic channels. The relevant markers could be
detected quickly at a low concentration of 500pgml−1
in a complex medium containing
human serum, and the chip could be used multiple times. As another example, extracellular
vesicles are abundant in various biological fluids, such as blood, saliva, urine, and extracellular
matrix. Toxic signals derived from extracellular vesicles can spread on tissues adjacent to the
damaged area in some diseases, including brain tumors and neurodegenerative disorders. In
this regard, extracellular vesicles that can be used clinically for liquid biopsy, needs to be better
characterized. An LSPR biosensor containing self-assembly gold nanoislands (SAM-AuNIs)
was used to detect and differentiate SH-SY5Y from microvesicles isolated from A-549 cells
[39]. Blood serum, lung cancer cell, and urine samples obtained from the mouse model were
used as biological samples. Exosomes have been shown to produce a discernible response in
the LSPR biosensor compared to microvesicles. According to these results, there was a differ-
ent biophysical interaction between exosomes and microvesicles with SAM AuNIs.
In addition to their single-mode measurements, LSPR sensors can be integrated with
different modalities. For instance, a dual-mode plasmonic biosensor that combines plas-
monic photothermal effect and LSPR sensing transduction has been developed as a
promising alternative method for the diagnosis of COVID-19 disease [40]. On this sensor,
SARS-CoV-2-specific sequences can be detected precisely using 2D AuNIs functionalized](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-21-320.jpg)
![1.5 Raman Spectroscopy and SER 7
with complementary DNA receptors. When the thermoplasmonic heat was illuminated
at the same AuNI chip at plasmonic resonance frequencies, a more sensitive sensing
performance was provided.
1.5
Raman Spectroscopy and SERS
Raman spectroscopy is a method that measures the frequency shifts of the inelastic diffuse
light from the sample when the photons hit a molecule and produce a diffused photon [41].
The photons of the laser light are absorbed successively by the sample, and the wavenum-
bers of re-sent photons are shifted up or down compared to the original monochrome
waves (termed as the Raman effect). The resultant shift provides information about vibra-
tion, rotation, and other low wavelength transitions in molecules [42]. Near-IR (NIR), vis-
ible, or UV range monochromatic light is usually utilized for the Raman effect, which
defines the photons to be adapted to virtual energy states, or energy stock generated due to
the interaction of light with vibration modes associated with chemical bonds in the sample.
Discrete vibration modes of the polarizable molecules are analyzed with such changes in
energy, thereby obtaining a qualitative measurement of the biochemical composition [43].
Raman spectroscopy is a powerful analytical technique used in many areas, including
detection of illegal drugs [44–46], toxic substances in the environment [47–49], and chemi-
cal [50–52] and biological warfare agents [53, 54], as well as ex vivo and in vivo applications
of tissue diagnosis [55–58], and biomedical applications in which in vitro drug–cell interac-
tion studies [59–62] are performed.
Resonance Raman effects that provide 102
–106
enhancement, and Surface Enhanced
Raman spectroscopy (SERS) resulting in up to 108
or both used together, which can provide
up to 1016
enhancement, are used to increase the Raman signal [63]. SERS phenomenon is
based on reduced Raman scattering when an analyte is adsorbed onto metal surface. The
differences between SERS and Raman technique are represented in Figure 1.4. From the
time when the discovery of the SERS, many researchers have begun to apply this method
for molecular-level analysis, taking advantages of SERS, including high sensitivity, unique
molecular fingerprint, and narrow spectral bandwidth for multiplex detection [64]. Known
as an ultra-sensitive method that can detect even single molecules, SERS has long been
considered a powerful tool, including the analysis of biomarkers that have been present in
trace amounts. It offers an exceptional “signature” spectrum profile with very narrow
peaks, capable of detecting multiple analytes simultaneously [65].
Laser light
Laser light
Rayleigh scattering
Rayleigh scattering
Metallic nanostructures
SERS technique
Raman technique
Analyte
Enhanced
Raman
Scattering
Raman
scattering
Figure 1.4 Basic principles of Raman and SERS technique. Source: Adapted and redrawn according
to Zheng and He [66]. © John Wiley & Sons.](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-22-320.jpg)
![1 Deciphering Plasmonic Modality to Address Challenges in Disease Diagnostics
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As a couple of examples in recent literature, a SERS sensor was fabricated using an
Ag nanorod array by combining molecular signatures in the form of special hairpin to
detect lung cancer-related miRNA biomarkers. With a portable-sized sensor, three dif-
ferent miRNAs (miRNA-21, miRNA-486 and miRNA-375) related to lung cancer were
detected qualitatively and quantitatively [65]. As another example, a new paper-based,
surface-enhanced SERS detection platform was developed to detect two key cytokines
related to atherosclerosis, causing many cardiovascular and cerebrovascular diseases
[67]. Two key cytokines, i.e., Interleukin 10 and monocyte chemoattractant protein 1,
play key roles in the progression of this disease at different levels, and they are used for
monitoring status and early diagnosis. A nanoporous networking membrane as a sub-
strate and SERS nanotags as a signal reading probe were designed as a sandwich strat-
egy, thereby enabling precise and specific identification of cytokine targets in human
serum. In another study, ultrasonic surface-assisted SERS biosensor of the target-
bound, acute myocardial infarction-related miRNA (miR-133a) was developed for the
detection of disease-related biomarkers [68]. Bimetallic probes with high stability and
a strong surface plasmon resonance effect were captured with a duplex connector to
perform signal amplification after synthesis with a controllable silver and gold ratio
through a galvanic replacement method. In this way, the target miR-133a could be
detected in a wide linear range with high selectivity compared to other miRNAs
expressed in human heart. The multiplex detection of biomarkers of Alzheimer’s dis-
ease is of great importance for early diagnosis and personalized treatment of the dis-
ease. As the last example here, different Raman dye coded polyA aptamer–AuNPs
conjugates were employed as SERS agents for simultaneous detection of Ap (1–42)
oligomers and Tau protein [69]. Here, specific protein-aptamer binding mediated
aggregation of AuNPs and the accompanying plasmonic coupling effect enabled to
detect protein biomarkers within 15 minutes.
1.6
Whispering Gallery Mode (WGM)
Basically, WGM sensors are resonating micro- or nano-structures that provide high qual-
ity factors (Q). Where the changes in Q or shear resonance wavelength is used to evaluate
surrounding milieu or binding events on the WGM resonator’s surface. Optical WGMs
are a family of electromagnetic modes built in a resonator with axial symmetry. WGMs
create resonances at certain frequencies that depend on the geometry of the resonator,
the refractive indices of both the resonator and the surrounding environment, and also
the polarization of the modes [70]. WGM resonators can be fabricated in different mor-
phologies with specific spectral properties, such as narrow line width, high stability, and
adjustability [71].
WGM-based sensors have been used to detect biological molecules; for instance, a plat-
form monitoring the shifts in the WGM resonance frequency were fabricated to measure
enzymatic oxidation of glucose (Figure 1.5) [72]. The platform was modified with glucose
oxidase and gold nanoparticles. Throughout the enzymatic reaction catalyzed by glucose
oxidase, electrons were transferred to gold nanoparticles, and the optical signals produced](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-23-320.jpg)
![1.7 Fiber Cables Sensor 9
by WGM resonators consisting of standard telecommunication fiber optics dissolved in a
hydrogen flame were evaluated. As a result of tests that were performed at various glucose
concentrations, the WGM-resonance frequency shift rate increased significantly at higher
glucose concentrations.
In another study, a WGM resonator-based on fluorescence imaging has been reported to
detect CA-125, i.e., an ovarian cancer biomarker [73]. Measurements have been extended
using a simplified approach to initiate WGM resonances through excitation light coupled
with the Dove prism. The mod structure in each resonator emerges thanks to the improved
phase matching, thereby providing significant improvements in signal-to-noise. In addi-
tion, fluorescence imaging of the WGM resonances enabled for repeatable detection of
biomarkers in complex biological fluids.
1.7
Fiber Cables Sensors
In recent years, the applications of fiber optic sensors in modern medical technologies and
devices have been leveraged. Since the first generation of probes for in vivo pressure detec-
tion has been commercialized, the research is underway to develop new generation of fiber
optic systems that have been significantly improved over the other sensing technologies,
such as micro- and nanoelectromechanical systems [74]. Usually, a fiber optic probe is
functionalized using biorecognition elements that can be selectively linked with target
molecules. In the system, the response occurs based on a change in the local refractive
index caused by the target. The biorecognition elements generally include various protein
and nucleic acid-based molecules. The label-free detection methods using optical fibers
enable to reach very low target detection limits. Gold, silver, magnetic nanoparticles and
nanostructures with different shapes and sizes can be used as energy concentrators to
expand the detection limits of optical fibers and obtain high-precision biosensing probes
[75]. Fiber optic biosensors reliant on SPR [76–78], long-period grating [79–81] and fiber
Bragg grating have been employed in a variety of fields and they provide rapid and precise
detection [82].
Liquid glucose
solution drop
GGG prism
Teflon tub
Frequency (MHz)
Intensity
(a.u.)
7 000 8 000 9 000 10 000
3600 s
3000 s
2400 s
1800 s
1200 s
600 s
0 s
0
400
800
1200
Photo-
diode
Peltier element
WGMR
780 nm
laser
Glucose
oxidase
layer
Lens
Au nano-
particles
Figure 1.5 Schematic representation of WGM-based glucose sensor. Source: Reprinted with
permission from Brice et al. [72]. © 2020, Elsevier.](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-24-320.jpg)
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As an example, fiber optic-based SPR type platform was utilized to detect acetylcho-
line, a pivotal neurotransmitter involved in the regulation of behavioral activities in
human [83]. Dysfunction in acetylcholine regulation, for instance, has been linked to a
variety of neurological disorders, including Alzheimer’s disease. In this study, the sens-
ing probe consisted of multiple layers of silver metal and tantalum-v-oxide nanoflakes
functionalized with acetylcholinesterase on the uncoated core of an optical fiber. Once
the sensing probe was exposed to acetylcholine solutions, the RI changed, and accord-
ingly, the sensor provided a detection limit down to 38 nM of acetylcholine. In another
study, a black phosphorus fiber optic biosensor was developed for the ultrasensitive
detection of human neuron-specific enolase (a cancer biomarker) [84]. Bio-
functionalized black phosphorus nanosheets by poly-l-lysine were exploited by inte-
grating them into a largely curved fiber grid. After the nanosheets were synthesized by
a liquid ultrasonication exfoliation, they were deposited on the fiber device by a layer-
by-layer method. The anti-NSE immobilized BP-TFG biosensor was able to detect small
cell lung cancer with a detection limit of 1.0 pg ml−1
. A new non-invasive measuring
probe based on the fiber Bragg grid (FBG) was designed as a hybrid multi-channel fiber
optic sensor system [85]. The probe specifically monitored body temperature, breathing
rate, and heart rate, and it was capable of processing signals coming up to 128 people
continuously (Figure 1.6).
(i) (ii)
Conector to another
probe
Conector to OSA
FBG2
FBG1
Measuring probe
(a)
(b)
Figure 1.6 (a) The fiber-optic probe. (b) (i) A schematic diagram of the experimental set up.
(ii) Experimental set up to acquire vital signals from a human subject using the probe embedded in
a thoracic elastic strap. Source: Reprinted with permission from Fajkus et al. [85]. © MDPI.](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-25-320.jpg)
![Ishmael
Fisher
On being called upon the prisoner pleaded not guilty.
The jury having been duly empanelled and sworn, the Attorney-General
opened the case for the Crown.[A]
Evidence for the Prosecution.
Ishmael Fisher, examined by Mr. James—I am a wine
merchant. I attend races occasionally, and knew the deceased,
John Parsons Cook, for about two years. I was at Shrewsbury
Races in November, 1855, and I remember the race for the Shrewsbury
Handicap won with a mare called “Polestar,” the property of Mr. Cook.
That was on Tuesday, the 13th of November. I saw Mr. Cook, the deceased,
that day upon the course. He appeared in his usual health and spirits. At
Shrewsbury I stopped at the Raven Hotel. I know Palmer, the prisoner, very
well. I have known him a little longer than I have known Mr. Cook. Mr.
Cook and Mr. Palmer were also stopping at the Raven Hotel, and were
occupying a room near me. There was only a wooden partition between my
room and theirs. Between eleven and twelve on the night of Wednesday I
went into the sitting room, in which Mr. Cook and Mr. Palmer and Mr.
Myatt were. Myatt is a saddler at Rugeley, and is a friend of Palmer. They
each appeared to have some grog before them. In my presence Mr. Cook
asked Mr. Palmer to have some more brandy and water. Mr. Palmer said, “I
shall not have any more till you have drunk yours.” Mr. Cook said then, “I
will drink mine,” and he took up his glass and drank it at a drop, or he
might have made two drops of it. After he had drunk it he said, “There is
something in it.” He also said, “It burns my throat dreadfully.” Mr. Palmer
then got up and took up the glass. He sipped up what was left of the glass,
and said, “There is nothing in it.” There appeared to be certainly not more
than a teaspoonful left by Mr. Cook. At that time a Mr. Reid, whom I knew,
came in. He is a wine merchant, and attends races. After Palmer had put his
glass to his mouth and said, “There is nothing in it,” he handed the glass to
Reid, and asked him if he thought there was anything in it. The glass was
also handed to me. We each said the glass being so empty we could not
recognise anything. I said I thought there was rather a strong scent upon it,
only I could not detect anything besides brandy. About ten minutes after this
Cook retired from the room. Cook then came back and called me out of the](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-32-320.jpg)
![deduct the £200. That was the course of dealing between us, but I did not
settle that account, as it turned out.
[A] See Introduction, p. 2.
Cross-examined by Mr. Serjeant Shee—I have known Mr. Palmer a
little longer than Mr. Cook. I knew that they were a good deal connected
with racing transactions. They appeared to be very intimate, and were a
great deal together. They generally stayed at the same hotels. I knew that
Cook won considerably at Shrewsbury. I knew that “Polestar” was his mare.
I do not know whether Palmer also won. I saw Mr. Cook after the race on
the course. He appeared very much elated and gratified. “Polestar” won
easily. In the room to which I went in the evening, in which Mr. Cook, Mr.
Palmer, and Mr. Myatt were, I remember seeing a glass before Mr. Palmer
and before Mr. Cook. I could not answer for Myatt’s glass. I believe there
was one decanter on the table. I did not observe sufficiently the glasses to
see whether both had been drinking. Mr. Cook asked me to take some
brandy. I do not recollect drinking any, but I cannot positively remember. I
was not tipsy. I do not think I drank anything. I believe I am a good judge of
brandy by the smell. I smelt this glass, and said that it had a strong smell
about it, but I thought there was nothing in it unlike brandy. The glass was
perfectly empty, and had been completely drained. I had been in the
Unicorn in the evening before this occurred. I saw both Cook and Palmer at
the Unicorn on Wednesday night about nine o’clock, or between nine and
ten. I cannot say if he was drinking then. I do not know that a good number
of people happened to be ill at Shrewsbury on that Wednesday or Tuesday. I
had a friend who was rather poorly there from a different kind of illness to
Mr. Cook. Wednesday was rather dull. I do not know that it rained, but it
was damp under foot I remember. I saw Mr. Cook about the racecourse
several times on Wednesday. On Thursday I remember the weather was
rather cold and damp, but I cannot say whether it rained or not. On the 16th
or 17th of November I received a letter from Mr. Cook, dated Rugeley, 16th
November, 1855—
Dear Fisher,—It is of very great importance to both Mr. Palmer and
myself that the sum of £500 should be paid to Mr. Pratt, of Queen Street,
Mayfair, to-morrow, without fail. £300 has been sent up to-night, and if you
will be kind enough to pay the other £200 to-morrow on receipt of this, you](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-34-320.jpg)
![Palmer perhaps four or five times in Cook’s room. I heard him say to Mr.
Cook that he would send over some broth. I did not see it brought over, but
I saw the broth in the kitchen. The cook told me that it had come over from
Mrs. Rowley. The broth had not been made at the Talbot Arms. Later in the
day I took up the broth to Mr. Cook. About a quarter of an hour after the
broth came over I met Palmer coming up the stairs to Cook’s room. He
asked if Cook had had his broth. I told him I did not know that any was
come for him. During this conversation Lavinia Barnes came forward and
said she had taken up the broth to Mr. Cook as soon as it had come, and he
had refused to take it, saying that it would not stay in his stomach. Palmer
said that I must go and fetch the broth, which I did, and took it into the
room. Mr. Palmer was there, and I left the broth in the room. About an hour
and a half afterwards I went up to the room again and found that the broth
had been vomited. About six o’clock that evening some barley water was
made for Cook. I took that up to him, but I cannot remember whether that
stayed in his stomach or not. At eight o’clock that evening I took up some
arrowroot to Cook. The first time I saw Mr. Bamford [the doctor at
Rugeley] was about three o’clock on the Saturday afternoon. Between
seven and eight on the Sunday morning I went into Mr. Cook’s room.
During the night Mr. Smith, a friend of Mr. Cook, had slept in the same
room. I asked Mr. Cook if he felt worse. He said he felt pretty comfortable,
and had slept well since twelve o’clock. Upon the Sunday a large breakfast
cup of broth was brought to the Talbot Arms by Charles Hawley. I took
some of it up to Mr. Cook’s room in the same cup in which it was brought. I
tasted about two tablespoonfuls of the broth before I took it up. It was
between twelve and one, before my dinner, that I tasted this broth. About
half an hour afterwards it made me very sick, and I vomited violently all the
afternoon till about five o’clock. I was obliged to go to bed. Up to that time
I had been quite well. I had taken nothing that I am aware of that had
disagreed with me. In the evening and on the morning of the Sunday I saw
Mr. Cook several times. He appeared to be better during that evening, and
to be in good spirits. The last time I saw him on the Sunday night might be
about ten or a little after that. I saw him between seven and eight on the
Monday morning. I took him up a cup of coffee. He did not vomit that.
Palmer was there that morning about a quarter or half-past seven. I saw him
coming downstairs as though he had been to see Mr. Cook. Mr. Cook got up
at one o’clock on that Monday. He appeared a great deal better, and he](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-37-320.jpg)
![E. Mills
by the bedside. He brought back with him some pills. He gave him
something else, but whether he brought it with him or not I do not know. He
gave him a drop from a wineglass after giving him the pills. Cook, when he
took the pills, said he could not swallow them. At Palmer’s request I gave
Cook a teaspoonful of toast and water, which he took. When I gave it him
from the spoon his body was then jerking and jumping. He snapped at the
spoon like that [describing it] with his head and neck, and the spoon was
fast between his teeth. It was difficult to get it away. He seemed to bite it
very hard. While this was going on the water went down his throat and
washed the pills down. Mr. Palmer then handed him the draught from the
wineglass. It was something liquid, and the wineglass was three parts full
with a liquid of a dark, heavy-looking nature. Cook drank it. He snapped at
the glass just the same as he did at the spoon. He swallowed the liquid,
which was vomited up immediately. I supported his forehead with my hand
while he vomited. The stuff he vomited smelt, I should think, like opium.
Palmer said that he hoped the pills were not returned, and he searched for
the pills with a quill. He said, “I cannot find the pills.” After this Cook
seemed to be more easy. This second attack lasted about half an hour, or it
might be more. He appeared to be conscious during the whole of that time.
He asked Palmer to feel his heart after he had got more composed. I do not
know whether he did so or not. Palmer made some slight remark as to its
being all right, or something of that kind. I left Cook and Palmer about
three o’clock in the morning. Cook was dozing when I left him, and Palmer
was asleep in the easy-chair.
I next saw Cook again about six o’clock on the Tuesday
morning. I said, “Has Mr. Palmer gone?” and he said, “Yes; he
left a quarter before five.” I asked him how he felt, and he said he
had been no worse since I left him in the morning. He asked me if I had
ever seen any one suffer such agony as he was in last night, and I said no, I
never had. I asked “What do you think was the cause of all that, Mr. Cook?”
and he said the pills that Palmer gave him at half-past ten. When I saw
Cook on the Tuesday morning I did not observe any of those jerkings or
convulsions about him. About twelve o’clock he rang his bell and desired
me to send the boots over to ask Palmer whether he might have a cup of
coffee. The boots returned and said he might have a cup of coffee, and that
Mr. Palmer would be over immediately. I took the coffee up a little after
twelve. Palmer was in Mr. Cook’s room at that time. I gave the coffee to](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-39-320.jpg)
![Mr. Palmer, who tasted the coffee in my presence. I then left the room. Mr.
Jones arrived by the three o’clock train that afternoon. He went and saw Mr.
Cook upon his arrival. About four, or it might be between four and five, I
took up to Mr. Cook’s room another cup of coffee. At that time I saw
Palmer in the room. I left the room, and afterwards I saw Palmer, who told
me that Mr. Cook had vomited the coffee. He spoke from the door of
Cook’s room, but did not call me in. I saw Cook several times that evening
before I retired to rest. He appeared to be in very good spirits, and talked
about getting up the next morning. I believe I gave him some arrowroot that
evening about half-past ten. Palmer was with him in his bedroom when I
left him. I gave Palmer a jug of toast and water for Cook. Mr. Palmer asked
Cook if I could do anything more for him that night, and Mr. Cook said he
would want nothing more. That was about half-past ten. I did not go to bed
that night, but I remained in the kitchen, as I was anxious to see how Mr.
Cook went on. While I was in the kitchen the bell of Mr. Cook’s room rang
violently a little before twelve [Tuesday night]. Mr. Jones was sleeping in
Cook’s bedroom, which was a double-bedded room, and where a bed had
been made up for him. I went upstairs to Mr. Cook’s room on hearing the
bell. He was sitting up in bed, and Mr. Jones appeared to be supporting him.
Mr. Cook said, “Oh, Mary, fetch Mr. Palmer directly.” He was conscious at
the time. I went over for Mr. Palmer. I rang the surgery bell at the surgery
door. I expected him to come to the window and as soon as I stepped off the
step into the road he was at the bedroom window. He did not put up the
sash. At that time I could not see whether he was dressed or not. I asked
him to come over to Mr. Cook directly, as he was much the same as he was
the night before. I then went back to the hotel. Palmer came two or three
minutes afterwards. I was in the bedroom when Palmer came, and he
remarked that he had never dressed so quickly in his life. That was the first
thing he said when he came into Cook’s room. Mr. Cook was sitting up in
bed, supported by Mr. Jones. After Mr. Palmer came I remained on the
landing, just outside the door. After I had been waiting a short time Palmer
came out. I said to him that Mr. Cook was much about the same as last
night, and he replied that he was not so ill by the fiftieth part. He then went
downstairs as though he was going into his own house, and after a very
short time he came back to Cook’s room. After Palmer had returned I heard
Cook ask to be turned over on his right side. I was at the door at the time,
which was open. I did not go in. I was not in the room when Cook died. I](https://image.slidesharecdn.com/19985-250402035923-a1d8c17b/85/Plasmonic-Sensors-and-their-Applications-Adil-Denizli-Editor-40-320.jpg)
Plasmonic Sensors and their Applications Adil Denizli (Editor)
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- 2. Here are some recommended products for you. Click the link to download, or explore more at ebookmass.com Molecular Imprinting for Nanosensors and Other Sensing Applications 1st Edition Adil Denizli (Editor) https://ebookmass.com/product/molecular-imprinting-for-nanosensors- and-other-sensing-applications-1st-edition-adil-denizli-editor/ Nanotechnology-Based Smart Remote Sensing Networks for Disaster Prevention Adil Denizli https://ebookmass.com/product/nanotechnology-based-smart-remote- sensing-networks-for-disaster-prevention-adil-denizli/ Biodegradable Materials and Their Applications Inamuddin https://ebookmass.com/product/biodegradable-materials-and-their- applications-inamuddin/ Nano-biosorbents for Decontamination of Water, Air, and Soil Pollution Adil Denizli & Nisar Ali & Muhammad Bilal & Adnan Khan & Tuan Anh Nguyen https://ebookmass.com/product/nano-biosorbents-for-decontamination-of- water-air-and-soil-pollution-adil-denizli-nisar-ali-muhammad-bilal- adnan-khan-tuan-anh-nguyen/
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- 5. Plasmonic Sensors and their Applications
- 6. Edited by Adil Denizli Plasmonic Sensors and their Applications
- 7. Editor Adil Denizli Department of Chemistry Hacettepe University Ankara Turkey Cover Cover Design: Wiley Cover Image: © Creations/Shutterstock All books published by WILEY‐VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at <http://dnb.d‐nb.de>. © 2021 WILEY‐VCH GmbH, Boschstr. 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Print ISBN: 978‐3‐527‐34847‐3 ePDF ISBN: 978‐3‐527‐83033‐6 ePub ISBN: 978‐3‐527‐83035‐0 oBook ISBN: 978‐3‐527‐83034‐3 Typesetting Straive, Chennai, India Printing and Binding Printed on acid‐free paper 10 9 8 7 6 5 4 3 2 1
- 8. v Preface xi 1 Deciphering Plasmonic Modality to Address Challenges in Disease Diagnostics 1 Esma Derin, Özgecan Erdem, and Fatih Inci 1.1 Introduction 1 1.2 Surface Plasmon Polaritons 2 1.2.1 Excitation of the SPP 3 1.3 Surface Plasmon Resonance (SPR) 4 1.4 Localized Surface Plasmon Resonance (LPSR) 5 1.5 Raman Spectroscopy and SERS 7 1.6 Whispering Gallery Mode (WGM) 8 1.7 Fiber Cables Sensors 9 1.8 New Trends in Plasmonic Sensors for the Applications in Disease Diagnosis 11 1.8.1 Mobile Phone-Integrated Platforms 11 1.8.2 Smart Material Integration 12 1.8.3 Naked-Eye Detection 16 1.9 Outcomes and Conclusion 18 References 19 2 Nanosensors Based on Localized Surface Plasmon Resonance 23 Deniz Umut Yildirim, Amir Ghobadi, and Ekmel Ozbay 2.1 Historical and Theoretical Background 23 2.2 Fabrication of Metal Nanostructures 29 2.3 Improving Detection Limit of LSPR Sensors 31 2.4 Integration of LSPR with Other Molecular Identification Techniques 34 2.4.1 Metal-Enhanced Fluorescence 34 2.4.2 Surface-Enhanced Raman Spectroscopy 37 2.4.3 Matrix-Assisted Laser Desorption Ionization Mass Spectroscopy 39 2.5 Practical Issues 39 2.6 Conclusions and Future Prospects 43 References 44 Contents
- 9. Contents vi 3 Highly Sensitive and Selective Plasmonic Sensing Platforms 55 Yeşeren Saylan and Adil Denizli 3.1 Introduction 55 3.2 What Is Highly Sensitive (Ultrasensitive)? 56 3.3 Plasmonic Sensing Platforms 56 3.4 Recent Applications 57 3.4.1 Medical Applications 57 3.4.2 Environmental Applications 61 3.5 Conclusion Remarks 67 References 67 4 Plasmonic Sensors for Detection of Chemical and Biological Warfare Agents 71 Semra Akgönüllü, Yeşeren Saylan, Nilay Bereli, Deniz Türkmen, Handan Yavuz, and Adil Denizli 4.1 Introduction 71 4.2 Sensors 72 4.2.1 Plasmonic-based Sensors 72 4.3 Biological Warfare Agents 72 4.3.1 Detection of Biological Warfare Agents 73 4.4 Chemical Warfare Agents 79 4.4.1 Detection of Chemical Warfare Agents 79 4.5 Conclusion and Future Perspective 81 References 82 5 A Plasmonic Sensing Platform Based on Molecularly Imprinted Polymers for Medical Applications 87 Neslihan Idil, Monireh Bakhshpour, Sevgi Aslıyüce, Adil Denizli, and Bo Mattiasson 5.1 Introduction 87 5.2 Molecular Imprinting Technology 88 5.3 Plasmonic Sensing 89 5.4 Medical Applications 91 5.4.1 Drug Detection Via MIP-based SPR Sensor 91 5.4.2 Hormone Detection Via MIP-based SPR Sensor 94 5.4.3 Microorganism and Virus Detection Via MIP-based SPR Sensor 95 5.4.4 Antibody Detection Via MIP-based SPR Sensor 96 5.4.5 Nucleic Acid Detection Via MIP-based SPR Sensor 97 5.4.6 Biomarker Detection Via MIP-based SPR Sensor 97 5.5 Conclusion 97 References 100 6 Magnetoplasmonic Nanosensors 103 Recep Üzek, Esma Sari, and Arben Merkoçi 6.1 Introduction 103 6.2 Synthesis 104
- 10. Contents vii 6.2.1 Core–Shell or Core–Satellite 105 6.2.2 Heterodimers 107 6.2.3 Multicomponent Doped Hybrids 108 6.3 Biosensing Applications 109 6.3.1 Protein 109 6.3.2 Pathogens 111 6.3.3 DNA 112 6.4 Conclusion 113 Acknowledgments 114 References 114 7 Plasmonic Sensors for Vitamin Detection 121 Duygu Çimen and Nilay Bereli 7.1 Introduction 121 7.1.1 Vitamins 121 7.2 Plasmonic Sensors 122 7.2.1 Surface Plasmon Resonance Sensors 123 7.2.2 Localized Surface Plasmon Resonance Sensors 124 7.2.3 Colorimetric Sensors 125 7.3 Vitamin Applications of Plasmonic Sensors 125 7.4 Conclusions and Prospects 133 References 133 8 Proteomic Applications of Plasmonic Sensors 137 Duygu Çimen, Merve Asena Özbek, Nilay Bereli, and Adil Denizli 8.1 Introduction 137 8.2 Plasmonic Sensors 139 8.2.1 Surface Plasmon Resonance Sensors 140 8.2.2 Localized Surface Plasmon Resonance 140 8.2.3 Colorimetric Sensors 142 8.3 Proteome Applications with Plasmonic Sensors 142 8.3.1 Food Applications 142 8.3.2 Biomedical Applications 145 8.3.3 Agricultural Applications 151 8.3.4 Oncology Applications 152 8.4 Conclusions and Prospects 154 References 154 9 Cancer Cell Recognition via Sensors System 157 Monireh Bakhshpour, Melek Özsevgiç, Ayşe Kevser Pişkin, and Adil Denizli 9.1 Introduction 157 9.2 Sensors Systems in Cancer Cell Detection 158 9.3 Cancer Cells 158 9.3.1 Prostate Cancer 159
- 11. Contents viii 9.3.2 Liver Cancer 160 9.3.3 Breast Cancer 160 9.3.4 Lung Cancer 164 9.3.5 Ovarian Cancer 164 9.3.6 Other Cells 165 9.4 Conclusion 168 References 168 10 Ultrasensitive Sensors Based on Plasmonic Nanoparticles 171 Ilgım Göktürk, Fatma Denizli, Erdoğan Özgür, and Fatma Yılmaz 10.1 Introduction 171 10.2 SPR and LSPR 173 10.3 SERS 176 10.4 Colorimetric Sensing 178 10.5 Luminescence Applications 179 10.6 Conclusion 180 References 181 11 Surface-Enhanced Raman Scattering Sensors for Chemical/Biological Sensing 189 Huma Shaikh, Zaib un Nisa Mughal, Saeed Memon, and Shahabuddin Memon 11.1 Introduction 189 11.2 Direct Method 192 11.3 Indirect Method 193 11.4 SERS-based Chemical Sensors (Chemosensors) 193 11.5 Absolute Intensity-based Method 195 11.6 Wavenumber Shift-based Method 195 11.7 Ratiometric Method 196 11.8 SERS-based Biological Sensors (Biosensors) 197 11.9 Conclusion 202 References 202 12 Carbon Nanomaterials as Plasmonic Sensors in Biotechnological and Biomedical Applications 209 Tahira Qureshi, Kemal Ҫetin, and Adil Denizli 12.1 Introduction 209 12.1.1 Graphene 210 12.1.2 Carbon Nanotubes 210 12.2 Biomedical and Biotechnological Applications of Carbon Nanomaterials as Plasmonic Sensors 211 12.2.1 Graphene-based Plasmonic Sensors 211 12.2.2 Carbon Nanotube-based Plasmonic Sensors 214 12.3 Final Statement and Further Outlook 215 References 217
- 12. Contents ix 13 Surface Plasmon Resonance Sensors Based on Molecularly Imprinted Polymers 221 Cem Esen and Sergey A. Piletsky 13.1 Introduction 221 13.1.1 Surface Plasmon Resonance 221 13.1.2 Molecularly Imprinted Polymers 222 13.2 MIP Based SPR Sensors 222 13.2.1 MIP Film Based SPR Sensors 223 13.2.2 Molecularly Imprinted Polymer Nanoparticles Based SPR Sensors 225 13.3 Conclusions and Future Prospects 229 References 230 Index 237
- 13. xi I welcome the publication of this book titled Plasmonic Sensors and Their Applications. In recent years, plasmonic sensors have been employed for various applications from medical diagnosis, environmental monitoring, pharmaceutical analysis, food quality detection to defense, and security fields. The development and progress of the plasmonic sensors cover chemistry, physics, material science, nanotechnology, and engineering. A huge body of information on plasmonic sensors and applications is already existed and continuing to create more reliable, selective, sensitive, and low‐cost sensors for a variety of applications although a complicated and time‐consuming production procedure. This book contains 13 chapters, which contain plasmonic sensors prepared by different methods and used for various applications. In the first chapter, following the mention of the fundamentals of plasmonic sensors, new trends in plasmonic sensors for the applica- tions in disease diagnosis are extensively reviewed with future perspectives. In Chapter 2, nanosensors based on localized surface plasmon resonance are highlighted. The historical and theoretical background, fabrication of metal nanostructures, improving detection limit, and integration of sensors with other molecular identification techniques are dis- cussed. Highly sensitive and selective plasmonic‐sensing platforms in medical and envi- ronmental applications are comprehensively evaluated in Chapter 3. The next chapter, Chapter 4, concentrates on the detection of chemical and biological warfare agents using plasmonic sensors with recent studies. Chapter 5 includes plasmonic‐sensing platforms based on molecularly imprinted polymers for medical applications. Chapter 6 summarizes the performance and analytical features of the magnetoplasmonic sensors. In Chapter 7, overview of vitamin detection using plasmonic sensors can be found. Proteomic applica- tions of plasmonic sensors are reviewed in Chapter 8. Cancer cell recognition via plas- monic sensor systems is given in Chapter 9. Plasmonic nanoparticles, which are prepared by different strategies for the ultrasensitive sensing platforms, are combined in Chapter 10. The next chapter, Chapter 11, gives details about the application of surface‐enhanced Raman scattering sensors for chemical and biological sensing. Carbon nanomaterials as plasmonic sensors in biotechnological and biomedical applications are summarized in Chapter 12. Finally, surface plasmon resonance sensors based on molecularly imprinted polymers are highlighted in detail in Chapter 13. Preface
- 14. Preface xii I believe this book provides an overview and highlights some of the recent research including the extensively studied topics. I would like to deeply thank WILEY‐VCH and all the contributors to the generation of this book possible. I hope this book will reach a broad range of readers. Prof. Dr. Adil Denizli Editor Ankara, Turkey, 2021
- 15. Visit https://ebookmass.com today to explore a vast collection of ebooks across various genres, available in popular formats like PDF, EPUB, and MOBI, fully compatible with all devices. Enjoy a seamless reading experience and effortlessly download high- quality materials in just a few simple steps. Plus, don’t miss out on exciting offers that let you access a wealth of knowledge at the best prices!
- 16. Plasmonic Sensors and their Applications, First Edition. Edited by Adil Denizli. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH. 1 1 1.1 Introduction Recent advances in health technologies have remarkable impact on health-care system. Advanced health technologies are however not affordable and available for resource- constraint settings. From global health perspective, recent improvements in health tech- nologies need to reflect alternative solutions for overcoming such inequalities by developing new technologies and strategies in the manners of cost-effective, rapid, easy-to-use, and portable size, hereby minimizing the disparities between resource-rich and limited settings [1, 2]. In this regard, biosensing arena has enormous applications in diverse fields, span- ning from biomedicine to agriculture; for instance, monitoring vital information for dis- eases detection or determining the presence of contaminants in water and soil [2]. The concentrations of analytes can be accurately determined based on a linear association between signal intensity and analyte concentrations via an analytical biosensor. In the field, four types of biosensors, such as optical (mostly plasmonic sensors), electrochemical, piezoelectric, and magnetic biosensor, are mainly employed for analytical measurements [3]. Optical biosensors (e.g. surface plasmon resonance (SPR), localized SPR (LSPR), surface-enhanced Raman scattering (SERS), plasmon-enhanced fluorescence (PEF), surface-enhanced infrared absorption spectroscopy (SEIAS), etc.) are some of the mostly applied biosensors in health-care biomedicine [4, 5]. Especially, SPR-stemmed platforms have been benefitted in a vast majority of bio-analytical analyses since this technique ena- bles rapid observation of bio-analytes in specimens, at the same time provides high sensi- tivity and selectivity in comparison to currently available instruments [2, 6]. These sensors basically monitor minute alterations in spectral properties of the plasmon by acting as a transducer of the sensing signal [5]. The sensing mechanism is constituted by recognizing and capturing the target analytes through bioreceptor which are immobilized on the metal surface. Then local refractive index increases due to capturing and SPR signals are shifted [7]. Their plasmonic fashion can be designed by considering the material and plasmonic features, like surface-based strategies that support SPP mode or nanoparticle-based Esma Derin1,2 , Özgecan Erdem1 , and Fatih Inci1,2 1 UNAM-National Nanotechnology Research Center, Bilkent University, Ankara, Turkey 2 Institute of Materials Science and Nanotechnology, Bilkent University, Ankara, Turkey Deciphering Plasmonic Modality to Address Challenges in Disease Diagnostics
- 17. 1 Deciphering Plasmonic Modality to Address Challenges in Disease Diagnostics 2 modality that employs localized surface plasmon resonance (LSPR). The intensity and peak position of the SPR have been influenced by the size, shape, and composition of the nano- structures and also the surrounding environment’s dielectric properties. [5].To touch upon the fundamentals of plasmonic sensors, they are stemmed from surface plasmon polariton (SPPs) or plasmonics, which are basically defined as the collective oscillations of free electrons at the metal surface [8]. Plasmonics deal with the electromagnetic (EM) wave and free electron inter- actions through excitation on conductors, such as metals, semimetals or semiconductors [9]. The excited electrons leads to collective oscillation with the close frequency to EM wave [9]. The history of SPP modality takes back more than a century, however, the improve- ments in the field have not accelerated until notable leaps in the nanotechnology (e.g. nanoscale fabrication techniques) to achieve appropriate sized structures for the further discoveries [10]. For instance, importantly note here, Kretschmann and Otto are two pioneers to create Surface Plasmon Resonance (SPR) through coupling strategies. Afterwards, SPR-based sensor was leveraged by Liedberg et al. through the antibody and antigen relations, which can be identified as a critical direction for biosensing platforms [11]. Today, SPR has been considered as one of the most powerful biosensing platforms, especially in analytical chemistry and medicine [7]. 1.2 Surface Plasmon Polaritons SP is the propagating light waves at the conductor surface via trapping due to interactions with free electrons [12]. Per these interactions, collective oscillations with light waves result in a resonance as a response of free electrons [12]. The formation of the SP is carried out by the resonant interactions of surface charge oscillations and electromagnetic field of light, and these interactions enhance the dominancy of SPs simultaneously [12]. The defi- nition of the SPP can be simplified as an electromagnetic wave, and more specifically, it is transverse magnetic (TM)-polarized optical surface wave that propagates directly along a surface between dielectric and a metal surface (Figure 1.1a) [13, 14]. In addition, metal surfaces have crucial charge density wave, which constitutes SPPs with the combination with electromagnetic fields that are maximum at the interface on the contrast through both media since they are decreased exponentially [14]. The amplitude of the SPP is influ- enced inversely (exponential decay) with the distance of each medium from the interface [13]. In addition to the metal surface, SPPs can be obtained from different metal struc- tures, such as thin films, stripes, differently sized and shaped nanoparticles or differently patterns (e.g. holes, slits, grooves, gaps, or corrugations, etc.) [14]. SPPs or plasmonics are mostly utilized by the fields of medical diagnostics, biosensing, spectroscopy, nanopho- tonic, imaging, or circuitry due to their substantial properties, including energy asymp- totes in dispersion curves, resonances, field enhancement and localization, high surface and bulk sensitivities, and subwavelength confinements [8, 14]. Another point is that SPPs have subwavelength property and field confinement since their ability is over- weighted to traditional optical elements (e.g. lenses, spatial light modulators) by consider- ing ability to spatial field modulations at nanoscale [8]. Majorly, Maxwell equations between interface of conductor (e.g. metals) and a dielectric layer are crucial for the inves- tigation of physical properties of SPPs [15].
- 18. 1.2 Surface Plasmon Polariton 3 The characteristics of the SP modes, which can be either localized SPs of individual par- ticles or several propagating SPPs on flat and curved, single and multiple surfaces, are determined by the topology of the metal surface. In addition, SPP modes of complex parti- cle arrays and metal nanostructures are also determined. Based on this unique property of the SPP-based waveguides, the bandwidth of information can be transported by plasmonic waveguides through conventional (dielectric-based) photonics. The interest in plasmon- based nanophotonics is increased substantially [16]. When the SPP interacts with the metal, its energy dissipates. Free electron scattering in the metal, which is bounded with an ideal dielectric, creates loss due to absorption via inter-band transitions at a short enough wavelength [14]. For the SPP, this loss is fundamental. Operating wavelength selection can be selected carefully to avoid absorption via inter-band transitions or advanced fabrication techniques can decrease the free-electron scattering, and however, the both cannot be elim- inated [14]. As aforementioned, surface of the metal interface has influence on the SPP, and moreover, the roughness creates additional loss since SPPs are scattered into bulk waves [14]. The main drawbacks of this loss are limiting practical applications of SPPs when it is excessive [14]. 1.2.1 Excitation of the SPP The excitation of the surface plasmon is mostly related to the conservation of the energy and momentum of photon in the incident light on a metal−dielectric interface. The excitation of the SPPs requires the momentum and energy matching to the incident photon’s and plasmon Detector Detector Angle Wavelength Extinction Reflectance Reflected light Incident light Electromagnetic field Electrons cloud Nanoparticle Dielectric Light Evanescent wave SPP Dielectric Surface plasmons on planar thin film–dielectric interface Surface plasmons on nanoparticle–dielectric interface plasmonic-active thin fim Light Prism θ (a) (b) Figure 1.1 (a) SPP propagation is illustrated through thin film with the surface charges at the metal and dielectric interface with the excitation, and the spectra is obtained after surface plasmon excitation. (b) SPP is generated through nanoparticle surface to achieve localized surface plasmon resonance (LSPR), and the spectra is obtained after surface plasmon excitation. Source: Reprinted with permission from Bhattarai et al. [19]. © MDPI.
- 19. 1 Deciphering Plasmonic Modality to Address Challenges in Disease Diagnostics 4 modes in order to obtain charge-coupled oscillations [17]. Special techniques are the primary requirement for the excitation of three-dimensional light beams in order to employ phase- matching [15]. The excitation of surface charges route can be explained by the presence of metal and dielectric interfaces and incoming p-polarized wave, which is transverse mode of the parallel electric field vector to the interface with an angle. The incident wave reaches the interface and split into two waves that are propagated in different directions [18]. Effective plasmon generation is achieved with the optical coupling element integration into the system. Prism, grating, and waveguide coupling methods (Figure 1.2) are the widely used light coupling techniques in comparison to waveguide, photonic crystal, and fiber-optic based coupling. These applications utilize attenuated total reflection (ATR), light diffraction or evanescent wave coupling from waveguide modes [17]. 1.3 Surface Plasmon Resonance (SPR) SPR is an optical biosensor that relies on the refractive index change of sensor surface, denoting label-free and in real-time detection [2, 20]. The plasmonics can be defined basi- cally interaction of light with metals or metallic nanostructures; hence, this mechanism combines photonics and electronics to measure optical properties, e.g. spectra and refrac- tive index changes at the nanoscale [3]. The interests in SPR biosensors have been increased enormously over the years [21]. The application of the SPR mostly focuses on clinical diag- nostics, biological and pharmaceutical analysis, food quality and safety evaluation since it enables to monitor molecular interactions and quantify biomarkers, such as proteins, DNA or whole cells [22]. SPP or SP is the main requirement to induce SPR in the interface between the metal (e.g. gold or silver) and dielectric materials based on light excitation [22]. The generation of SPP in the form of EM wave occurs after the interactions of the incident light with metal since, col- lective oscillation of the free electrons is induced by the photons in the conduction band [23]. (a) (b) nprism > nL (c) (d) (e) (f) θSP θSP θSP1 θSP2 Figure 1.2 The common configuration of SPP excitations is depicted. (a) Kretschmann configuration, (b) two-layer Kretschmann configuration, (c) Otto configuration, (d) excitation with an SNOM probe, (e) grating diffraction, and (f) diffraction on surface features. Source: Reprinted with permission from Zayats et al. [24]. © 2005, Elsevier.
- 20. 1.4 Localized Surface Plasmon Resonance (LPSR 5 SPPs can be only sustained by p-polarized electromagnetic or transverse magnetic wave at an interface of metal and dielectric medium. The sign of the dielectric constant has to be oppo- site for instance gold, silver, copper, or aluminum, which have negative real and positive imaginary dielectric constants, and therefore, they can be used for the SPP generation [23]. These indicated metals have both pros and cons; for instance, the negative real dielectric constant of silver is the largest, which creates higher sensitivity against to refractive index (RI) changes. However, its chemical stability is lower due to easy oxidation in air. In contrast to silver, RI sensitivity of gold is lower, yet it holds higher stability and chemical versatility, and hence, the functionalization of the sensor surface can be carried out much easier. 1.4 Localized Surface Plasmon Resonance (LPSR) Localized surface plasmon resonance (LSPR) is an optical phenomenon produced as a result of interactions between the incoming light and surface electrons in a conduction band through a light wave trapped in conductive nanoparticles smaller than the wavelength of light. This phenomenon is reliant on the size, geometry, dielectric environment, composi- tion, and particle–particle separation distance of the nanoparticles [25]. Since metal nano- structures interact with a beam of light, some of the incoming photons are absorbed, and the rest are scattered in different directions. When LSPR is stimulated, these absorptions and scattering events increase greatly. In metal nanostructures, LSPR is most easily detected by an optical spectroscopic method, and this measurement is usually based on the extinction or scattering events [26]. The differences between SPR and LSPR are illustrated in Figure 1.3. In addition to gold and silver, which are the most commonly used plasmonic materials, the other metals, such as copper [27] and aluminum [28, 29] also exhibit plasmon reso- nance features [30]. Mostly, the physical properties of metal particles change considerably when the size of particles is around nanoscale, and also, smaller than the wavelength of Wavelength (nm) Particles θ λ Film SPR LSPR Ansorbance Reflectivity Angle (°) 450 60 70 80 65 75 500 550 600 650 Figure 1.3 The schematic represents the basic principle and the difference between SPR and LSPR. Source: Reprinted with permission from Jatschka et al. [37]. © Elsevier.
- 21. 1 Deciphering Plasmonic Modality to Address Challenges in Disease Diagnostics 6 light used to illuminate them [31]. In recent years, biosensors based on LSPR (majorly stemmed from metallic nanoparticles) have begun to draw attention for the label-free bio- sensing approaches due to its easy and colorimetric sensing features, as well as portability and its ability to interface with multiplexed devices [30, 31]. LSPR biosensors can also be easily integrated into miniaturized devices for point-of-care (POC) applications in order to save cost and reach the assay at different settings [32–34]. Integrating full-automation to these sensors also helps minimizing inter-personal errors for the measurements. Such inte- grations enable rapid acceleration for biosensor deployment into the health-care settings by promoting wider POC applications, such as bedside diagnosis, personalized medicine, and wearable devices [35]. Mostly, two main methods are used in LSPR biosensors: direct and indirect strategies. The first strategy tracks the shifts in the LSPR absorption peak due to the refractive index changes upon binding of the target molecule. This direct analysis requires less time and cost, but it has a limited sensitivity. The latter strategy is reliant on a sandwich analysis, where LSPR is used to stimulate the labels. As the light is on, metal nanostructures produce LSPR and are used to capture light near the surfaces [36]. On the other hand, there are also some obstacles. Since LSPR-based strategies are mostly dependent on the changes in the refractive index at the close vicinity of nanoparticles, a large number of molecules need to be localized around the particles in order to create a plasmonic shift. Strategies, such as adjusting the size and shape of the nanoparticle mate- rial, could be utilized to overcome this limit [30]. Another obstacle could be the reproduc- ibility of sensor surface comprised of nanoparticles, ultimately limiting their utility and expansion to hurdle the real-world problems in clinical use. From an application perspective, sensitive and selective detection of cancer biomarkers is of great importance in the early diagnosis of this disease. In a study, for instance, a LSPR lab-on- a-chip was designed to detect human alpha fetoprotein and prostate-specific antigen, which are cancer markers [38]. The microfluidic chip, which was developed by combining plas- monic, microfluidics, nanofabrication, and surface chemistry, accommodated 32 detection areas distributed across 8 independent microfluidic channels. The relevant markers could be detected quickly at a low concentration of 500pgml−1 in a complex medium containing human serum, and the chip could be used multiple times. As another example, extracellular vesicles are abundant in various biological fluids, such as blood, saliva, urine, and extracellular matrix. Toxic signals derived from extracellular vesicles can spread on tissues adjacent to the damaged area in some diseases, including brain tumors and neurodegenerative disorders. In this regard, extracellular vesicles that can be used clinically for liquid biopsy, needs to be better characterized. An LSPR biosensor containing self-assembly gold nanoislands (SAM-AuNIs) was used to detect and differentiate SH-SY5Y from microvesicles isolated from A-549 cells [39]. Blood serum, lung cancer cell, and urine samples obtained from the mouse model were used as biological samples. Exosomes have been shown to produce a discernible response in the LSPR biosensor compared to microvesicles. According to these results, there was a differ- ent biophysical interaction between exosomes and microvesicles with SAM AuNIs. In addition to their single-mode measurements, LSPR sensors can be integrated with different modalities. For instance, a dual-mode plasmonic biosensor that combines plas- monic photothermal effect and LSPR sensing transduction has been developed as a promising alternative method for the diagnosis of COVID-19 disease [40]. On this sensor, SARS-CoV-2-specific sequences can be detected precisely using 2D AuNIs functionalized
- 22. 1.5 Raman Spectroscopy and SER 7 with complementary DNA receptors. When the thermoplasmonic heat was illuminated at the same AuNI chip at plasmonic resonance frequencies, a more sensitive sensing performance was provided. 1.5 Raman Spectroscopy and SERS Raman spectroscopy is a method that measures the frequency shifts of the inelastic diffuse light from the sample when the photons hit a molecule and produce a diffused photon [41]. The photons of the laser light are absorbed successively by the sample, and the wavenum- bers of re-sent photons are shifted up or down compared to the original monochrome waves (termed as the Raman effect). The resultant shift provides information about vibra- tion, rotation, and other low wavelength transitions in molecules [42]. Near-IR (NIR), vis- ible, or UV range monochromatic light is usually utilized for the Raman effect, which defines the photons to be adapted to virtual energy states, or energy stock generated due to the interaction of light with vibration modes associated with chemical bonds in the sample. Discrete vibration modes of the polarizable molecules are analyzed with such changes in energy, thereby obtaining a qualitative measurement of the biochemical composition [43]. Raman spectroscopy is a powerful analytical technique used in many areas, including detection of illegal drugs [44–46], toxic substances in the environment [47–49], and chemi- cal [50–52] and biological warfare agents [53, 54], as well as ex vivo and in vivo applications of tissue diagnosis [55–58], and biomedical applications in which in vitro drug–cell interac- tion studies [59–62] are performed. Resonance Raman effects that provide 102 –106 enhancement, and Surface Enhanced Raman spectroscopy (SERS) resulting in up to 108 or both used together, which can provide up to 1016 enhancement, are used to increase the Raman signal [63]. SERS phenomenon is based on reduced Raman scattering when an analyte is adsorbed onto metal surface. The differences between SERS and Raman technique are represented in Figure 1.4. From the time when the discovery of the SERS, many researchers have begun to apply this method for molecular-level analysis, taking advantages of SERS, including high sensitivity, unique molecular fingerprint, and narrow spectral bandwidth for multiplex detection [64]. Known as an ultra-sensitive method that can detect even single molecules, SERS has long been considered a powerful tool, including the analysis of biomarkers that have been present in trace amounts. It offers an exceptional “signature” spectrum profile with very narrow peaks, capable of detecting multiple analytes simultaneously [65]. Laser light Laser light Rayleigh scattering Rayleigh scattering Metallic nanostructures SERS technique Raman technique Analyte Enhanced Raman Scattering Raman scattering Figure 1.4 Basic principles of Raman and SERS technique. Source: Adapted and redrawn according to Zheng and He [66]. © John Wiley & Sons.
- 23. 1 Deciphering Plasmonic Modality to Address Challenges in Disease Diagnostics 8 As a couple of examples in recent literature, a SERS sensor was fabricated using an Ag nanorod array by combining molecular signatures in the form of special hairpin to detect lung cancer-related miRNA biomarkers. With a portable-sized sensor, three dif- ferent miRNAs (miRNA-21, miRNA-486 and miRNA-375) related to lung cancer were detected qualitatively and quantitatively [65]. As another example, a new paper-based, surface-enhanced SERS detection platform was developed to detect two key cytokines related to atherosclerosis, causing many cardiovascular and cerebrovascular diseases [67]. Two key cytokines, i.e., Interleukin 10 and monocyte chemoattractant protein 1, play key roles in the progression of this disease at different levels, and they are used for monitoring status and early diagnosis. A nanoporous networking membrane as a sub- strate and SERS nanotags as a signal reading probe were designed as a sandwich strat- egy, thereby enabling precise and specific identification of cytokine targets in human serum. In another study, ultrasonic surface-assisted SERS biosensor of the target- bound, acute myocardial infarction-related miRNA (miR-133a) was developed for the detection of disease-related biomarkers [68]. Bimetallic probes with high stability and a strong surface plasmon resonance effect were captured with a duplex connector to perform signal amplification after synthesis with a controllable silver and gold ratio through a galvanic replacement method. In this way, the target miR-133a could be detected in a wide linear range with high selectivity compared to other miRNAs expressed in human heart. The multiplex detection of biomarkers of Alzheimer’s dis- ease is of great importance for early diagnosis and personalized treatment of the dis- ease. As the last example here, different Raman dye coded polyA aptamer–AuNPs conjugates were employed as SERS agents for simultaneous detection of Ap (1–42) oligomers and Tau protein [69]. Here, specific protein-aptamer binding mediated aggregation of AuNPs and the accompanying plasmonic coupling effect enabled to detect protein biomarkers within 15 minutes. 1.6 Whispering Gallery Mode (WGM) Basically, WGM sensors are resonating micro- or nano-structures that provide high qual- ity factors (Q). Where the changes in Q or shear resonance wavelength is used to evaluate surrounding milieu or binding events on the WGM resonator’s surface. Optical WGMs are a family of electromagnetic modes built in a resonator with axial symmetry. WGMs create resonances at certain frequencies that depend on the geometry of the resonator, the refractive indices of both the resonator and the surrounding environment, and also the polarization of the modes [70]. WGM resonators can be fabricated in different mor- phologies with specific spectral properties, such as narrow line width, high stability, and adjustability [71]. WGM-based sensors have been used to detect biological molecules; for instance, a plat- form monitoring the shifts in the WGM resonance frequency were fabricated to measure enzymatic oxidation of glucose (Figure 1.5) [72]. The platform was modified with glucose oxidase and gold nanoparticles. Throughout the enzymatic reaction catalyzed by glucose oxidase, electrons were transferred to gold nanoparticles, and the optical signals produced
- 24. 1.7 Fiber Cables Sensor 9 by WGM resonators consisting of standard telecommunication fiber optics dissolved in a hydrogen flame were evaluated. As a result of tests that were performed at various glucose concentrations, the WGM-resonance frequency shift rate increased significantly at higher glucose concentrations. In another study, a WGM resonator-based on fluorescence imaging has been reported to detect CA-125, i.e., an ovarian cancer biomarker [73]. Measurements have been extended using a simplified approach to initiate WGM resonances through excitation light coupled with the Dove prism. The mod structure in each resonator emerges thanks to the improved phase matching, thereby providing significant improvements in signal-to-noise. In addi- tion, fluorescence imaging of the WGM resonances enabled for repeatable detection of biomarkers in complex biological fluids. 1.7 Fiber Cables Sensors In recent years, the applications of fiber optic sensors in modern medical technologies and devices have been leveraged. Since the first generation of probes for in vivo pressure detec- tion has been commercialized, the research is underway to develop new generation of fiber optic systems that have been significantly improved over the other sensing technologies, such as micro- and nanoelectromechanical systems [74]. Usually, a fiber optic probe is functionalized using biorecognition elements that can be selectively linked with target molecules. In the system, the response occurs based on a change in the local refractive index caused by the target. The biorecognition elements generally include various protein and nucleic acid-based molecules. The label-free detection methods using optical fibers enable to reach very low target detection limits. Gold, silver, magnetic nanoparticles and nanostructures with different shapes and sizes can be used as energy concentrators to expand the detection limits of optical fibers and obtain high-precision biosensing probes [75]. Fiber optic biosensors reliant on SPR [76–78], long-period grating [79–81] and fiber Bragg grating have been employed in a variety of fields and they provide rapid and precise detection [82]. Liquid glucose solution drop GGG prism Teflon tub Frequency (MHz) Intensity (a.u.) 7 000 8 000 9 000 10 000 3600 s 3000 s 2400 s 1800 s 1200 s 600 s 0 s 0 400 800 1200 Photo- diode Peltier element WGMR 780 nm laser Glucose oxidase layer Lens Au nano- particles Figure 1.5 Schematic representation of WGM-based glucose sensor. Source: Reprinted with permission from Brice et al. [72]. © 2020, Elsevier.
- 25. 1 Deciphering Plasmonic Modality to Address Challenges in Disease Diagnostics 10 As an example, fiber optic-based SPR type platform was utilized to detect acetylcho- line, a pivotal neurotransmitter involved in the regulation of behavioral activities in human [83]. Dysfunction in acetylcholine regulation, for instance, has been linked to a variety of neurological disorders, including Alzheimer’s disease. In this study, the sens- ing probe consisted of multiple layers of silver metal and tantalum-v-oxide nanoflakes functionalized with acetylcholinesterase on the uncoated core of an optical fiber. Once the sensing probe was exposed to acetylcholine solutions, the RI changed, and accord- ingly, the sensor provided a detection limit down to 38 nM of acetylcholine. In another study, a black phosphorus fiber optic biosensor was developed for the ultrasensitive detection of human neuron-specific enolase (a cancer biomarker) [84]. Bio- functionalized black phosphorus nanosheets by poly-l-lysine were exploited by inte- grating them into a largely curved fiber grid. After the nanosheets were synthesized by a liquid ultrasonication exfoliation, they were deposited on the fiber device by a layer- by-layer method. The anti-NSE immobilized BP-TFG biosensor was able to detect small cell lung cancer with a detection limit of 1.0 pg ml−1 . A new non-invasive measuring probe based on the fiber Bragg grid (FBG) was designed as a hybrid multi-channel fiber optic sensor system [85]. The probe specifically monitored body temperature, breathing rate, and heart rate, and it was capable of processing signals coming up to 128 people continuously (Figure 1.6). (i) (ii) Conector to another probe Conector to OSA FBG2 FBG1 Measuring probe (a) (b) Figure 1.6 (a) The fiber-optic probe. (b) (i) A schematic diagram of the experimental set up. (ii) Experimental set up to acquire vital signals from a human subject using the probe embedded in a thoracic elastic strap. Source: Reprinted with permission from Fajkus et al. [85]. © MDPI.
- 26. Visit https://ebookmass.com today to explore a vast collection of ebooks across various genres, available in popular formats like PDF, EPUB, and MOBI, fully compatible with all devices. Enjoy a seamless reading experience and effortlessly download high- quality materials in just a few simple steps. Plus, don’t miss out on exciting offers that let you access a wealth of knowledge at the best prices!
- 27. Exploring the Variety of Random Documents with Different Content
- 28. Palmer writes to Pratt that he must have “Polestar.” “ 22.Palmer goes to London and pays Pratt £100; he had no money at Shrewsbury, and lost on the races. “ 23.Palmer at Rugeley again; sees Cheshire, and desires him to witness a document purporting to be signed by Cook acknowledging £4000 of bills to have been negotiated by Palmer for Cook. Nov. 23.Mr. Stevens, Cook’s stepfather, arrives in Rugeley, sees Palmer, and discusses Cook’s affairs and the funeral. Cook’s betting book and papers not found. Coffin ordered by Palmer without Stevens’s knowledge. Stevens notices unusual appearance of the body; returns to London and consults a solicitor, who gives him introduction to Mr. Gardner, solicitor in Rugeley. Stevens and Palmer meet on the train from London to Rugeley, and Stevens informs Palmer that he intends to have a post-mortem.
- 29. “ 25.(Sunday) Palmer applies to Dr. Bamford for death certificate, which is given for apoplexy. Sends for Newton, and has a conversation about the effects of strychnia. “ 26.Post-mortem examination; Palmer is present, and acts suspiciously. Mr. Stevens takes jars, with contents from the body, to London for analysis to be made by Professor Taylor. Dec. 5.Cheshire, having opened Professor Taylor’s letter to Mr. Gardner, containing account of analysis, tells Palmer strychnia or other poisons, with the exception of traces of antimony, have not been found. “ 8.Palmer writes to the coroner as to Professor Taylor’s letter. “ 14.Inquest, at which Professor Taylor gives evidence. Verdict of “wilful murder” returned. Palmer, who was in custody of Sheriff’s
- 30. officer for the bills, is arrested on the verdict and taken to Stafford Gaol.
- 31. THE TRIAL. Within the Central Criminal Court, Old Bailey, London. Wednesday, 14th MAY, 1856. The Court met at Ten o’clock. ——— Judges— LORD CHIEF JUSTICE CAMPBELL. Mr. JUSTICE CRESSWELL. Mr. BARON ALDERSON. ——— Counsel for the Crown— The Attorney-General (Sir Alexander Cockburn). Mr. Edward James, Q.C. Mr. Bodkin. Mr. Welsby. Mr. Huddleston. ——— Counsel for the Prisoner— Mr. Serjeant Shee. Mr. Grove, Q.C. Mr. Gray. Mr. Kenealey. The prisoner, William Palmer, surgeon, of Rugeley, aged thirty-one was indicted for having at Rugeley, county of Stafford, on 21st November, 1855, feloniously, wilfully, and with malice aforethought, committed murder on the person of John Parsons Cook.
- 32. Ishmael Fisher On being called upon the prisoner pleaded not guilty. The jury having been duly empanelled and sworn, the Attorney-General opened the case for the Crown.[A] Evidence for the Prosecution. Ishmael Fisher, examined by Mr. James—I am a wine merchant. I attend races occasionally, and knew the deceased, John Parsons Cook, for about two years. I was at Shrewsbury Races in November, 1855, and I remember the race for the Shrewsbury Handicap won with a mare called “Polestar,” the property of Mr. Cook. That was on Tuesday, the 13th of November. I saw Mr. Cook, the deceased, that day upon the course. He appeared in his usual health and spirits. At Shrewsbury I stopped at the Raven Hotel. I know Palmer, the prisoner, very well. I have known him a little longer than I have known Mr. Cook. Mr. Cook and Mr. Palmer were also stopping at the Raven Hotel, and were occupying a room near me. There was only a wooden partition between my room and theirs. Between eleven and twelve on the night of Wednesday I went into the sitting room, in which Mr. Cook and Mr. Palmer and Mr. Myatt were. Myatt is a saddler at Rugeley, and is a friend of Palmer. They each appeared to have some grog before them. In my presence Mr. Cook asked Mr. Palmer to have some more brandy and water. Mr. Palmer said, “I shall not have any more till you have drunk yours.” Mr. Cook said then, “I will drink mine,” and he took up his glass and drank it at a drop, or he might have made two drops of it. After he had drunk it he said, “There is something in it.” He also said, “It burns my throat dreadfully.” Mr. Palmer then got up and took up the glass. He sipped up what was left of the glass, and said, “There is nothing in it.” There appeared to be certainly not more than a teaspoonful left by Mr. Cook. At that time a Mr. Reid, whom I knew, came in. He is a wine merchant, and attends races. After Palmer had put his glass to his mouth and said, “There is nothing in it,” he handed the glass to Reid, and asked him if he thought there was anything in it. The glass was also handed to me. We each said the glass being so empty we could not recognise anything. I said I thought there was rather a strong scent upon it, only I could not detect anything besides brandy. About ten minutes after this Cook retired from the room. Cook then came back and called me out of the
- 33. room, and I went with him into my sitting room. Cook at that time was very ill. He had been sick. He said he had been very sick, and he thought that Palmer had dosed him. On that occasion he handed me over a sum of money, between £700 and £800 in bank notes. It was given to me to be taken care of. He did not say till when. Mr. Palmer and Mr. Cook jointly occupied a sitting room. They occupied different bedrooms. After Cook had given me this money he was immediately seized with sickness. I saw him in the same room and in his own bedroom. He again complained of suffering during the time he was absent, and said he had been again very sick. He asked me to go with him to his bedroom, which I did. A Mr. Jones, a stationer, went with me to his bedroom. While we were there he was violently vomiting again, so much so that we thought it right to send for the doctor, Mr. Gibson. We left him that morning in his room about two o’clock or a little after. Mr. Gibson came about half-past twelve or a quarter to one. I again sent for Mr. Gibson, as Cook was so ill. The second time I sent was about one, as near as I can remember. After taking some medicine Cook became more composed. The medicine was sent by Mr. Gibson, but he did not administer it himself. Mr. Jones and myself gave him the medicine. The next morning about ten o’clock I saw Palmer in my own sitting room. He was in the sitting room when I got downstairs. He said that Cook had been stating he had given him something last night, that he had been putting something in his brandy, or something to that effect. Palmer said he never played such tricks with people. He said, “I can tell you what he was; he was very drunk.” Cook certainly was not drunk. I did not see him at dinner, but I saw him some time after, and from what I observed of him he was certainly sober. On the same morning Mr. Cook came up to my bedroom after he had got up. He was looking very ill. I gave him back his money. On that day (Thursday) I saw Mr. Cook on the racecourse at Shrewsbury. It would be about three o’clock. He looked very ill. I frequently had been in the habit of settling his bets for him when he did not settle them himself. I was in the habit of paying and receiving for him at Tattersall’s and other places. At Shrewsbury I saw Cook’s betting book in his possession. It was a little more than half the size of this (a small memorandum book). As nearly as I can remember, it was very nearly this colour (a dark colour). On the 17th, which was Saturday, I paid to Mr. Pratt, by direction of Mr. Cook, £200 in a cheque. As his agent I expected to settle his Shrewsbury account at Tattersall’s on the following Monday, and I should have been entitled to
- 34. deduct the £200. That was the course of dealing between us, but I did not settle that account, as it turned out. [A] See Introduction, p. 2. Cross-examined by Mr. Serjeant Shee—I have known Mr. Palmer a little longer than Mr. Cook. I knew that they were a good deal connected with racing transactions. They appeared to be very intimate, and were a great deal together. They generally stayed at the same hotels. I knew that Cook won considerably at Shrewsbury. I knew that “Polestar” was his mare. I do not know whether Palmer also won. I saw Mr. Cook after the race on the course. He appeared very much elated and gratified. “Polestar” won easily. In the room to which I went in the evening, in which Mr. Cook, Mr. Palmer, and Mr. Myatt were, I remember seeing a glass before Mr. Palmer and before Mr. Cook. I could not answer for Myatt’s glass. I believe there was one decanter on the table. I did not observe sufficiently the glasses to see whether both had been drinking. Mr. Cook asked me to take some brandy. I do not recollect drinking any, but I cannot positively remember. I was not tipsy. I do not think I drank anything. I believe I am a good judge of brandy by the smell. I smelt this glass, and said that it had a strong smell about it, but I thought there was nothing in it unlike brandy. The glass was perfectly empty, and had been completely drained. I had been in the Unicorn in the evening before this occurred. I saw both Cook and Palmer at the Unicorn on Wednesday night about nine o’clock, or between nine and ten. I cannot say if he was drinking then. I do not know that a good number of people happened to be ill at Shrewsbury on that Wednesday or Tuesday. I had a friend who was rather poorly there from a different kind of illness to Mr. Cook. Wednesday was rather dull. I do not know that it rained, but it was damp under foot I remember. I saw Mr. Cook about the racecourse several times on Wednesday. On Thursday I remember the weather was rather cold and damp, but I cannot say whether it rained or not. On the 16th or 17th of November I received a letter from Mr. Cook, dated Rugeley, 16th November, 1855— Dear Fisher,—It is of very great importance to both Mr. Palmer and myself that the sum of £500 should be paid to Mr. Pratt, of Queen Street, Mayfair, to-morrow, without fail. £300 has been sent up to-night, and if you will be kind enough to pay the other £200 to-morrow on receipt of this, you
- 35. Thomas Jones George Reid will greatly oblige me. I will settle it on Monday at Tattersall’s. I am much better. I received this on the 17th at No. 4 Victoria Street, London. I considered that Palmer and Cook were for some time jointly connected with racing transactions, but there is no proof of it. Cook was not more elated after winning than people usually are. Thomas Jones, examined by Mr. Welsby—I am a law stationer, and was at Shrewsbury Races last November. I stayed at the Raven. On the Monday night Cook supped with me and some other friends. He appeared well on that occasion, as he also did on the Tuesday and Wednesday. On Wednesday night, between eleven and twelve, Mr. Cook came into my room at the Raven and invited me into his. I went there, and found, amongst other people in the room, Palmer. After the party broke up Mr. Fisher said something to me about Cook, in consequence of which I went up to Cook’s bedroom. I found him there, and he complained of a burning in his throat. He was vomiting. Some pills and a draught were brought. Mr. Cook refused to take the pills, in consequence of which I went to the doctor, Mr. Gibson, and got some liquid medicine from him, which I brought back and gave to Mr. Cook. He drank about a wineglassful of the medicine, and after that he also took some of the pills. Next morning, between six and seven, I again saw him. He looked pale, and appeared to be unwell. George Reid, examined by Mr. Bodkin—I was acquainted with the deceased Mr. Cook and the prisoner Palmer. I saw them at Shrewsbury Races in November. On the Tuesday and Wednesday Cook appeared to be in his usual health. On Wednesday night I went into the room at the Raven where Palmer and Cook were. There was another gentleman present. We had a glass of brandy and water before the time to rest. Almost immediately after I arrived there I noticed that Cook was in pain. I heard him say to Mr. Palmer there was something in the brandy and water. Mr. Palmer handed me the glass to taste from it. I said, “What is the use of handing me the glass when it is empty?” The next time I saw Cook was about eleven o’clock the next morning. He said he was very ill.
- 36. W. S. Gibson E. Mills Cross-examined by Serjeant Shee—I should consider that Cook’s general state of health was delicate. He always had a pallid complexion, and did not look like a strong man. William Scafe Gibson, examined by Mr. Huddleston—I am assistant to Mr. Heathcote, surgeon, at Shrewsbury. On 14th November last, between twelve and one at night, I was sent for to the Raven Hotel, and saw there Mr. Cook in his bedroom. He was not in bed. He complained of pain in his stomach and heat in his throat, and said he thought he had been poisoned. His pulse was about 90; his tongue was perfectly clean. I advised him to take an emetic, which he did, and he was then very sick. Nothing came away but water. I sent him two pills and a draught. The pills consisted of rhubarb and 3 grains of calomel. The draught consisted of mistura sennacum. Later on in the same night I gave Mr. Jones some medicine for Cook. I never saw Cook after that occasion. Cross-examined by Mr. Serjeant Shee—I treated Cook as if he had taken poison. I took him at his word, that he had taken poison, not from his symptoms. He seemed a little excited by drink. Elizabeth Mills, examined by Mr. James—I was chambermaid at the Talbot Arms at Rugeley in November last. I had been there about two years. I knew the prisoner. He was in the habit of coming to the Talbot Arms. I remember on Thursday, the 15th, between nine and ten at night, Mr. Cook, along with Mr. Palmer, came to the Talbot Arms. He retired to rest between ten and eleven. He said he had been poorly, and was feeling poorly then. The next morning he got up about twelve o’clock, and said he felt no worse, but still he was not well. That night he retired to bed about half-past ten. He said he had been to Mr. Palmer’s and had dined there. On Saturday morning about eight, Palmer, who lived opposite to the Talbot Arms, came over. He ordered a cup of coffee for Mr. Cook, which I believe I gave to Mr. Cook in his bedroom. Mr. Palmer was in the room at the time. I did not see Cook drink it, but about half an hour afterwards I returned into the room and found that the coffee had been vomited. On that occasion I observed a jug in the room which did not belong to the Talbot Arms. It was sent down to me by Lavinia Barnes to make some more toast and water. During that Saturday I saw
- 37. Palmer perhaps four or five times in Cook’s room. I heard him say to Mr. Cook that he would send over some broth. I did not see it brought over, but I saw the broth in the kitchen. The cook told me that it had come over from Mrs. Rowley. The broth had not been made at the Talbot Arms. Later in the day I took up the broth to Mr. Cook. About a quarter of an hour after the broth came over I met Palmer coming up the stairs to Cook’s room. He asked if Cook had had his broth. I told him I did not know that any was come for him. During this conversation Lavinia Barnes came forward and said she had taken up the broth to Mr. Cook as soon as it had come, and he had refused to take it, saying that it would not stay in his stomach. Palmer said that I must go and fetch the broth, which I did, and took it into the room. Mr. Palmer was there, and I left the broth in the room. About an hour and a half afterwards I went up to the room again and found that the broth had been vomited. About six o’clock that evening some barley water was made for Cook. I took that up to him, but I cannot remember whether that stayed in his stomach or not. At eight o’clock that evening I took up some arrowroot to Cook. The first time I saw Mr. Bamford [the doctor at Rugeley] was about three o’clock on the Saturday afternoon. Between seven and eight on the Sunday morning I went into Mr. Cook’s room. During the night Mr. Smith, a friend of Mr. Cook, had slept in the same room. I asked Mr. Cook if he felt worse. He said he felt pretty comfortable, and had slept well since twelve o’clock. Upon the Sunday a large breakfast cup of broth was brought to the Talbot Arms by Charles Hawley. I took some of it up to Mr. Cook’s room in the same cup in which it was brought. I tasted about two tablespoonfuls of the broth before I took it up. It was between twelve and one, before my dinner, that I tasted this broth. About half an hour afterwards it made me very sick, and I vomited violently all the afternoon till about five o’clock. I was obliged to go to bed. Up to that time I had been quite well. I had taken nothing that I am aware of that had disagreed with me. In the evening and on the morning of the Sunday I saw Mr. Cook several times. He appeared to be better during that evening, and to be in good spirits. The last time I saw him on the Sunday night might be about ten or a little after that. I saw him between seven and eight on the Monday morning. I took him up a cup of coffee. He did not vomit that. Palmer was there that morning about a quarter or half-past seven. I saw him coming downstairs as though he had been to see Mr. Cook. Mr. Cook got up at one o’clock on that Monday. He appeared a great deal better, and he
- 38. washed and dressed and shaved himself. He said he felt exceedingly weak. On the Monday Ashmall, the jockey, and Mr. Saunders, Cook’s trainer, visited him. As soon as Cook got up at one o’clock I gave him some arrowroot, which he retained in his stomach. I believe he had a cup of coffee about four or five. About eight o’clock that night Miss Bond, the housekeeper, gave me a pillbox to take upstairs to Mr. Cook’s room, which I did, and placed it on the dressing-table. It was wrapped up in white paper. I do not know whether the box contained pills or not. After I had placed the pillbox on Cook’s dressing-table Palmer came, and went into Cook’s room. I saw him sitting down by the fire between nine and ten. I retired to rest between ten and eleven. About a quarter or ten minutes before twelve Lavinia Barnes, the waitress, called me up. I heard a noise of violent screaming whilst I was dressing. The screams came from Cook’s room. My room is on the floor above Cook’s room. I heard the screams twice, and went down to Cook’s room. As soon as I entered the room I found him sitting up in bed. He desired me to fetch Mr. Palmer directly. I walked to his bedside, and I found the pillow upon the floor. There was one mould candle burning. I picked up the pillow and asked him would he lay down his head. At that time he was sitting up and was beating the bed-clothes, with both his arms and hands stretched out. He said, “I cannot lie down. I shall suffocate if I do. Oh, fetch Mr. Palmer.” His body, his hands, and neck were moving then—a sort of jumping or jerking. His head was back. Sometimes he would throw back his head upon the pillow, and then he would raise himself up again. This jumping and jerking was all over his body. He appeared to have great difficulty in breathing. The balls of both the eyes were much projected. It was difficult for him to speak, he was so short of breath. He screamed three or four times while I was in the room. He called aloud “Murder” twice. He asked me to rub one hand. I found the left hand stiff. It appeared to be stretched out as though the fingers were something like paralysed. It did not move. It appeared to me to be stiff all the way up his arm. I did not rub him very long. The stiffness did not appear to be gone after I had rubbed him. During the time I was rubbing his hands Palmer was in the room. Cook was conscious while this jerking of the body was going on. He recognised Palmer when he came in, and said, “Oh, Palmer, I shall die,” or “Oh, doctor, I shall die.” Palmer replied, “Oh, my lad, you won’t.” Palmer then left to fetch something, and asked me to stay by the bedside with him. He returned in a few minutes, during which time I merely stood
- 39. E. Mills by the bedside. He brought back with him some pills. He gave him something else, but whether he brought it with him or not I do not know. He gave him a drop from a wineglass after giving him the pills. Cook, when he took the pills, said he could not swallow them. At Palmer’s request I gave Cook a teaspoonful of toast and water, which he took. When I gave it him from the spoon his body was then jerking and jumping. He snapped at the spoon like that [describing it] with his head and neck, and the spoon was fast between his teeth. It was difficult to get it away. He seemed to bite it very hard. While this was going on the water went down his throat and washed the pills down. Mr. Palmer then handed him the draught from the wineglass. It was something liquid, and the wineglass was three parts full with a liquid of a dark, heavy-looking nature. Cook drank it. He snapped at the glass just the same as he did at the spoon. He swallowed the liquid, which was vomited up immediately. I supported his forehead with my hand while he vomited. The stuff he vomited smelt, I should think, like opium. Palmer said that he hoped the pills were not returned, and he searched for the pills with a quill. He said, “I cannot find the pills.” After this Cook seemed to be more easy. This second attack lasted about half an hour, or it might be more. He appeared to be conscious during the whole of that time. He asked Palmer to feel his heart after he had got more composed. I do not know whether he did so or not. Palmer made some slight remark as to its being all right, or something of that kind. I left Cook and Palmer about three o’clock in the morning. Cook was dozing when I left him, and Palmer was asleep in the easy-chair. I next saw Cook again about six o’clock on the Tuesday morning. I said, “Has Mr. Palmer gone?” and he said, “Yes; he left a quarter before five.” I asked him how he felt, and he said he had been no worse since I left him in the morning. He asked me if I had ever seen any one suffer such agony as he was in last night, and I said no, I never had. I asked “What do you think was the cause of all that, Mr. Cook?” and he said the pills that Palmer gave him at half-past ten. When I saw Cook on the Tuesday morning I did not observe any of those jerkings or convulsions about him. About twelve o’clock he rang his bell and desired me to send the boots over to ask Palmer whether he might have a cup of coffee. The boots returned and said he might have a cup of coffee, and that Mr. Palmer would be over immediately. I took the coffee up a little after twelve. Palmer was in Mr. Cook’s room at that time. I gave the coffee to
- 40. Mr. Palmer, who tasted the coffee in my presence. I then left the room. Mr. Jones arrived by the three o’clock train that afternoon. He went and saw Mr. Cook upon his arrival. About four, or it might be between four and five, I took up to Mr. Cook’s room another cup of coffee. At that time I saw Palmer in the room. I left the room, and afterwards I saw Palmer, who told me that Mr. Cook had vomited the coffee. He spoke from the door of Cook’s room, but did not call me in. I saw Cook several times that evening before I retired to rest. He appeared to be in very good spirits, and talked about getting up the next morning. I believe I gave him some arrowroot that evening about half-past ten. Palmer was with him in his bedroom when I left him. I gave Palmer a jug of toast and water for Cook. Mr. Palmer asked Cook if I could do anything more for him that night, and Mr. Cook said he would want nothing more. That was about half-past ten. I did not go to bed that night, but I remained in the kitchen, as I was anxious to see how Mr. Cook went on. While I was in the kitchen the bell of Mr. Cook’s room rang violently a little before twelve [Tuesday night]. Mr. Jones was sleeping in Cook’s bedroom, which was a double-bedded room, and where a bed had been made up for him. I went upstairs to Mr. Cook’s room on hearing the bell. He was sitting up in bed, and Mr. Jones appeared to be supporting him. Mr. Cook said, “Oh, Mary, fetch Mr. Palmer directly.” He was conscious at the time. I went over for Mr. Palmer. I rang the surgery bell at the surgery door. I expected him to come to the window and as soon as I stepped off the step into the road he was at the bedroom window. He did not put up the sash. At that time I could not see whether he was dressed or not. I asked him to come over to Mr. Cook directly, as he was much the same as he was the night before. I then went back to the hotel. Palmer came two or three minutes afterwards. I was in the bedroom when Palmer came, and he remarked that he had never dressed so quickly in his life. That was the first thing he said when he came into Cook’s room. Mr. Cook was sitting up in bed, supported by Mr. Jones. After Mr. Palmer came I remained on the landing, just outside the door. After I had been waiting a short time Palmer came out. I said to him that Mr. Cook was much about the same as last night, and he replied that he was not so ill by the fiftieth part. He then went downstairs as though he was going into his own house, and after a very short time he came back to Cook’s room. After Palmer had returned I heard Cook ask to be turned over on his right side. I was at the door at the time, which was open. I did not go in. I was not in the room when Cook died. I
- 41. E. Mills went in, I believe, just before he died, but I came out again. I saw Mr. Jones supporting Cook. Mr. Palmer was then feeling Mr. Cook’s pulse, and he said to Mr. Jones, “His pulse is gone.” Mr. Jones pressed the side of his face to Cook’s heart. Mr. Palmer asked me to fetch Mr. Bamford, and I did so. From the time I was called up, about ten minutes before twelve, till Cook’s death would be about three-quarters of an hour. Mr. Bamford came over, and I saw him when he came downstairs. He said, “He is dead. He was dead when I arrived.” Mr. Jones came out of the room and told me that Mr. Palmer wanted me. I went into the room and saw Mr. Palmer. There was no one with him. I said, “It is not possible Mr. Cook is dead,” and he said, “Oh, yes, he is dead.” He asked me to arrange about laying out Cook. I had seen a book in Mr. Cook’s room, a dark book with a gold band round the edge. It had a pencil going into it on one side. Cook stopped at the Talbot Arms perhaps two or three months before this time. I saw the book on the Monday night before Mr. Cook’s death. He wrote something in it, and took from a pocket in the book a postage stamp. I placed the book back at the looking-glass on the dressing-table. I have never seen that book since Cook’s death. I have searched everywhere for it. When I went into the room where Cook’s body was lying Palmer was there. I noticed that Cook’s clothes were placed on a chair. I saw Palmer searching the pocket. That was on the Tuesday night about ten minutes after Cook’s death. He also searched under the pillow and bolster. After Cook’s death I saw some letters on the mantelpiece which were not there before. The Court then adjourned. Second Day, Thursday, 15th May, 1856. The Court met at ten o’clock. Elizabeth Mills, cross-examined by Mr. Serjeant Shee—I had been at the Talbot Arms about three years at the date of Mr. Cook’s death. He first came to the Talbot Arms about three months before he died, and up to the time of his death he was constantly coming back and forward. During the time he was there I never heard him complain of anything except a sore throat or something of that kind through cold. I never noticed that he had any soreness about his mouth or that he
- 42. E. Mills had difficulty at all in swallowing. I have seen him with a foul tongue about once or so. He never complained in my hearing of the tongue being sore so as to render it difficult to swallow. I do not know of caustic having been applied to it while he was there. Before he went to Shrewsbury he had not been ailing at all to my knowledge. When he came back he said he was poorly. After Cook’s death I stayed at the Talbot Inn till the day after Christmas. I then went to my home in the Potteries, Shelton. Since then I have been in service in Dolly’s Hotel, Paternoster Row, London. I stayed six weeks there as chambermaid. About a week after I came to London I saw Mr. Stevens (the stepfather of Cook) about six or seven times. Two or three times I saw him alone; at other times perhaps Mrs. Dewhurst, the landlady of the inn, or Miss Dewhurst was there. It was not always about Mr. Cook’s death that he spoke to me. He would merely call to see how I liked London, and whether I was well in health, and all that. Mr. Stevens is a man not in your station. He is a gentleman. Do you mean to say he called to see how you liked London?— Just to see whether I liked the place. I had some conversation with him at the Talbot Inn just before the funeral. I really cannot remember what he spoke about beyond Mr. Cook’s death. During the time I was at Dolly’s Hotel I never received a farthing from him, and he never made me any promise to get a place. The last time I saw him out of Court was on Tuesday last at Dolly’s Hotel. He never spoke to me about Mr. Cook’s death. When I saw him at that time there were other people present, including Lavinia Barnes, Mr. Gardner, and Mr. Hatton, the chief officer of police in Staffordshire. Mr. Gardner is an attorney at Rugeley. I cannot say what all the talk was about. Mr. Cook’s death might be mentioned. I daresay it was. I will undertake to say that there were other subjects of conversation between us besides the subject of Cook’s death. I do not wish to mention what they were. They did not, so far as I heard, talk about the evidence I was to give. They did not ask me what I could prove, nor did they read my depositions before the coroner to me. There was nothing read to me from a newspaper or anything else. Mr. Stevens never at any previous interview read anything from a newspaper to me. He never talked to me about the symptoms which Mr. Cook exhibited before his death. Before last Tuesday I had seen Mr. Hatton about twice. I saw him once at Dolly’s, when he dined there. I did not wait upon him. I merely saw him there. He might have talked about Mr. Cook’s death, but I cannot remember. I have seen Mr.
- 43. E. Mills Gardner there three or four times since Mr. Cook’s death. I have seen him at Dolly’s, and have met him in the street. I have merely said, “How do you do,” or “Good morning.” I have had no other talk with him. I do not remember to have read the case of a Mrs. Dove in the newspapers, but I may have done so. I have heard spoken of a case that lately occurred at Leeds of a lady who was said to have been poisoned by her husband, but I did not read it. It was not mentioned to me by Mr. Stevens, nor by Mr. Gardner, nor by Mr. Hatton. Were you told when you heard of it what the symptoms of Mrs. Dove were?—I think not. I merely heard there had been strychnine used at Leeds, another strychnine case. Were the symptoms of strychnine ever mentioned to you by any one?— No, never. When, and to whom, did you first use the expression “twitching,” which you mentioned so repeatedly yesterday?—To the coroner, I did. If I did not mention twitching, I mentioned something to the same effect. I will not swear I used that word at the coroner’s. I cannot remember when I first used the word “twitching.” I cannot remember when I first used the word “jerking” to anybody. I will undertake to swear it has never been used to me by anybody. You stated yesterday that on the Sunday some broth was brought in a breakfastcup between twelve and one o’clock; that you took it up to Cook’s bedroom; that you drank about two tablespoonfuls; that you were sick the whole afternoon, and vomited till five o’clock. Did you state one word about that in your deposition before the coroner?—It never occurred to me until three days afterwards. Did you state before the coroner that there was nothing peculiar in the taste of the broth?—I believe I was examined three times before the coroner. My attention had been called to the fact of broth having been sent over on one occasion, but I do not remember whether it was the first. I was asked if I had tasted it, and I stated I had tasted it, and thought it was very good. It never occurred to me to mention that I was sick and vomited frequently in the course of the afternoon. You went to bed in consequence of the vomiting?—Yes. I suppose sickness of that kind repeated frequently in the course of an afternoon is not a very common occurrence with
- 44. you?—No, I have a bilious attack sometimes, but not such violent vomiting as I had that afternoon. I could not at all account for it at the time. I only took two tablespoonfuls. The vomiting came on from half an hour to an hour after I took them. On the Saturday morning did Cook express a wish to have coffee for breakfast, or was it from Palmer the first you heard that his breakfast was to be coffee?—I do not know whether Palmer told me to bring coffee or whether it was Cook. I never knew Mr. Cook to take coffee in bed before. He generally took tea. I understood you to say yesterday Palmer came over at eight o’clock and ordered a cup of coffee for Cook. Do you adhere to that?—I cannot remember whether Palmer ordered it or not. If I said it yesterday it is correct, but I cannot remember whether Palmer ordered the coffee or not now. I will swear now that Palmer ordered the coffee, and I took it and gave it into Cook’s hands, and Palmer was there. You swear to it now?—Yes. You doubted it a moment ago?—If that was stated yesterday I do not doubt it was correct. Is that your only reason for stating it to be correct?—I believe it to be correct. Will you swear that it is correct?—Yes; it is no doubt correct if I said so. Why should that make it more correct if you cannot say it now from your own recollection?—I cannot remember as well to-day as I did yesterday. I cannot remember that I stated before the coroner that Cook had coffee for breakfast at eight o’clock, that he ate nothing, and that he vomited directly he had swallowed it, and that up to the time I had given him the coffee I had not seen Palmer. I cannot remember whether I stated before the coroner anything about the pillbox on Monday night. It was sent over wrapped up in paper. I will swear that Palmer was there between nine and ten o’clock. He brought a jar of jelly to the Talbot, and I opened it. I should say he was there nearer to ten than nine. I do not recollect whether he was there when I left Cook at half-past ten. You stated yesterday that you asked Cook on the Tuesday afternoon what he thought the cause of his illness was, and he said, “The pills which Palmer gave me at half-past ten”?—Yes. Did you say that before the coroner?—No.
- 45. E. Mills Have you been questioned by any one since Mr. Cook’s death respecting what you did say before the coroner as to when these pills might have been given or respecting anything you have said about these pills before the coroner?—Yes; I was questioned by Dr. Collier at Hitchingly. I did not tell him that the gentleman in London had altered my evidence on that point, and that my evidence was now to be that “Cook said the pills which Palmer gave him at half-past ten made him ill.” Did he state anything about your evidence being altered since?—Yes; he said he had not got that down in what I had given to the coroner in the coroner’s papers. I said “No, I thought it was down in some of the papers. I had given it to a gentleman in London.” The evidence has been altered by myself since. I do not remember who the gentleman was that I had given it to. I gave it to him at Dolly’s. The gentleman came to me at Dolly’s and asked if I would answer him a few questions. I said I would, and I saw him in a sitting-room. I was with him about half an hour. He asked me not very many questions, and during the time I was answering the questions he was writing. He did not tell me who he was or whom he came from, but he mentioned Mr. Stevens’ name. What did he say about Mr. Stevens?—Mr. Stevens was with him. He called Mr. Stevens by name. Why did you not tell us that before?—You did not ask me. Then, although you did not know who he was, you knew he was an acquaintance of Mr. Stevens because he came with him?—He did. All that I said then was taken down. I do not remember saying before the coroner that when Cook was ill on Monday night and sitting up in bed beating the bed- clothes he said, “I cannot lie down; I shall suffocate if I do.” I do not remember whether I mentioned the word “jerking” before the coroner. Did you say before the coroner, “He would throw his head back and raise himself up again”?—Yes. You will say you said that?—Yes. I do not know whether I mentioned the word “jerking.” I said the whole of the body was in a jumping, snatching way. I believe I mentioned it was difficult for him to speak, he was so short of breath. I did not mention about him calling “murder” twice. I do not remember whether I mentioned before the coroner that Mr. Cook said the pills stuck fast in his throat and he could not swallow them. I did
- 46. E. Mills J. Gardne r not answer the coroner anything more than he asked me. If he had asked me I should have answered him as I am answering now. The first time that you were examined before the coroner was Dr. Taylor present?—I believe he was. Were you not recalled after you had been examined once for the purpose of describing the symptoms for Dr. Taylor to hear?—I was not. I was never examined as to the symptoms when I knew the medical gentlemen were there. I cannot remember how Mr. Palmer was dressed when he came over on the Tuesday night. He had a plaid dressing- gown on, but I cannot remember what sort of cap he had. When Mr. Jones asked me to go into the room after Mr. Cook’s death I went in at once, and it was then that I saw Palmer searching the pockets of the coat. When I went in he did not seem at all confused. Re-examined by Mr. James—I was under examination before the coroner perhaps a couple of hours on different occasions. The coroner put the questions to me, and the coroner’s clerk, I believe, wrote down my answers. The coroner asked me if the broth had any effect on me, and I said not that I was aware of. By Mr. Serjeant Shee—What brought to your mind afterwards the vomiting after taking the broth?—I do not know. I believe it was some one else in the house that mentioned my sickness first. It did not occur to me until some one else mentioned it about a week after the coroner was there. Re-examination resumed—I cannot remember who it was, but it was some of my fellow-servants in the house. A person of the name of Dr. Collier called upon me and represented that he was for the Crown. He asked me questions about the inquest and about the death of Mr. Cook. That would be about three weeks or a month ago, at Hitchingley. James Gardner, examined by the Attorney-General—I am an attorney, and attended for Mr. Stevens at the inquest. The inquest lasted five days, and on each of these days I had several times occasion to expostulate with Mr. Ward, the coroner, as to questions which he put or omitted to put, and I observed that the clerk omitted to take down answers given to the questions which had been put. Cross-examined by Mr. Serjeant Shee—A great many questions were put by the jury after the examination of the professional men.
- 47. Anne Brooks By the Attorney-General—The jury made very strong observations as to the necessity for further questions. Objection to statement of these observations allowed. Mrs. Anne Brooks, examined by the Attorney-General—I live in Manchester, and am in the habit of attending race meetings. I was at Shrewsbury races in November, 1855. About eight o’clock in the evening of Wednesday, the 14th, I met Palmer in the street. I had some conversation with him as to horses that were running during that week at Shrewsbury. About half-past ten the same evening I went, along with some friends, to the Raven, where I knew Palmer was staying. I had been there frequently before. I left my friends downstairs and went upstairs to go to Palmer’s room, which I knew. As I approached Palmer’s room a servant called my attention to Palmer himself, who was standing at a small table in the passage. When I first saw him he had a glass tumbler in his hand, in which there appeared to be a small quantity of liquid like water. I did not see him put anything in the glass. I saw him shaking up the fluid that was in it. There was a light in the passage. It was nearer to me than to him. He held up the glass as if he were looking at the light through it. He then said to me, “I will be with you presently.” He noticed me the moment I got to the top of the stairs. After he made that remark to me he stood for a minute or two holding the glass in his hand up to the light once or twice and shaking it now and then. The only observation he made was about the fine weather we had. After this he carried the glass into a sitting room adjoining his own. The room, I imagined, was empty, as I heard no one speaking. He remained there two or three minutes, and came out with the glass still in his hand, and carried it into his own sitting room, shutting the door after him. Three or four minutes afterwards he came out to me, bringing me a glass—it might be the same one, it was very like it—with some brandy and water in it. I took the brandy and water, and it produced no unpleasant consequences in me. We had some conversation regarding the next day’s racing, and he said he should back his own horse “Chicken.” “Chicken” lost. Palmer never told me afterwards whether he had won or lost on the race. Cross-examined by Mr. Serjeant Shee—I am a married woman, and am in the habit of attending race meetings, but my husband does not sanction
- 48. Anne Brooks L. Barnes my going when he knows about it. Several people were taken ill in Shrewsbury on the Wednesday. One of my company was dreadfully ill, and there was a wonder what could cause it; we made an observation. We thought the water might have been poisoned. We were all affected the same way by sickness. Can you tell me in what way it affected persons? By the Attorney-General—Any person you saw. Whom did you see yourself affected in that way?—There was a lady that came to meet me there; she was one; and there was another party in my company who was so ill that he could not go to the races on Thursday. By Mr. Serjeant Shee—They were affected by sickness and purging. You saw Palmer with the glass in his hand?—I did. Did he put it up to the light?—He held it just carelessly up. I did not see any substance in the glass. He was doing this in a passage that led to a great many rooms. I could not say if there was more than one light in the passage. I think it was a chandelier. He said, “I will be with you presently,” when he carried the glass into the room which I supposed to have been unoccupied. Did he also say that while he was holding it to the light?—Yes, just in this manner, quite carelessly. And at that time you thought nothing of it?—I thought he was mixing up some cooling draught, and was waiting for some water. I was not examined before the coroner. By the Attorney-General—The brandy and water he gave me was cold, not hot. I have known Palmer for a great number of years as a racing man. Lavinia Barnes, examined by Mr. James—In November, 1855, I was in service as waitress at the Talbot Arms. I knew both Palmer and Mr. Cook. I saw Mr. Cook on 12th November on his way to the Shrewsbury Races. He seemed quite well then. I saw him on Thursday, the 15th, on his return from the races. On Friday I saw him between nine and ten, when he came back after having dined with Palmer. He was quite sober. I saw Mr. Cook twice on Saturday. On that day I remember some broth being sent over, which I took up to Mr. Cook. He
- 49. could not take it, as he said he was too sick. I brought the broth down to the kitchen. I saw Palmer, and told him that Cook would not take the broth, as he was too sick. Palmer said he must take it, and it was taken up again to him by Elizabeth Mills. I did not see any broth being brought over on the Sunday. Between twelve and one on the Sunday Elizabeth Mills was taken ill, and had to leave her work and go to bed. I saw her; she was vomiting violently. Between four and five she returned to work, and complained to me of having been ill from the vomiting. I saw some broth in a basin in the kitchen on the Sunday. I do not know where it was made. It was in a sick cup with two handles. The cup did not belong to the Talbot Arms, and it went back to Palmer’s. Between seven and eight on Sunday morning I heard Palmer say he was going to London on the Monday. On Monday I saw Cook after dinner. Mr. Saunders, the trainer, visited him, and I took up some brandy and water to them. On that night I slept in the room next Mr. Cook’s. I saw Palmer between eight and nine that night going upstairs in the direction of Cook’s room. I saw him in the room afterwards between twelve and one o’clock. About twelve o’clock I was in the kitchen, when Mr. Cook’s bell rang violently. I went up to his room, and found he was very ill. He asked me to send for Mr. Palmer. He was screaming “murder,” and was in violent pain. He said he was suffocating. His eyes looked very wild, and were standing a great way out of his head. He was beating the bed with his hands. I sent the boots for Palmer, and went and called Elizabeth Mills. After Palmer came I went up to the room again. Cook seemed to be more composed. Palmer told him not to be alarmed. I saw Cook drinking a darkish mixture in a glass. I cannot remember who gave it to him, but Palmer was in the room when it was given. When Cook put the glass to his mouth he snapped at it. I both saw and heard him do it. He vomited the black-looking draught. I left the room between twelve and one, and he seemed more composed then. I saw him again on the Tuesday, and he seemed to be much better. A few minutes before twelve o’clock on the Tuesday night Elizabeth Mills and I were in the kitchen. Mr. Cook’s bell rang, and Elizabeth Mills went up to answer it. I followed her upstairs, but did not go into the room. I heard Cook scream. Elizabeth Mills went for Palmer, and he came. He was dressed in his usual way, with a black coat on. There was nothing peculiar about his dress. He wore a cap. After Palmer went into the room I remained on the landing. I did not hear what was going on inside. Palmer came out and went downstairs for something. When he
- 50. came out Elizabeth Mills asked him how Mr. Cook was, and he replied, “Not so bad by a fiftieth part.” She and I were both together when he said this. I went into the room before Mr. Cook died. Mr. Jones was there in attendance upon him. Before I went into the room, and when Palmer was there, I heard Cook ask to be turned over. After I went into the room I do not remember hearing anything. I came out again before Cook’s death, and did not see him die. I returned to the room afterwards, and saw Palmer there with one of Cook’s coats in his hands. He was feeling the pockets. I also saw him feel under the bolster I left him in the room with the dead body. On the Thursday following I met Palmer in the hall of the hotel. He asked me for the key of Cook’s room, and I fetched it from the bar. He said he wanted some books and papers and a paper knife, which were to go back to the stationer’s where he had them from, or he should have to pay for them. I went into the room with him. While there he asked me to go to Miss Bond, the housekeeper, for some books she had. I brought them back with me to the room, and found Palmer there searching on the chest of drawers among some books and clothes belonging to Mr. Cook. I thought it was the paper knife he was looking for, as he said, “I cannot find the knife anywhere.” Miss Bond then came into the room, and I left. I saw Mr. Jones, who had visited Cook on the Tuesday, on the Friday with Palmer. I heard him ask Palmer if he knew where Cook’s betting book was. I cannot remember what Palmer replied. He said it would be sure to be found, and asked me and the chambermaid to go and look for it. He also said, “It was not worth anything to anybody but Cook.” This would be between three and four o’clock, and Mr. Stevens, who was at the Talbot Arms that day, left about half-past four. We went to look for the betting book. Palmer did not go with us. We searched under the bed and all round the room. We did not look in the chests of drawers, of which there were two in the room, both unlocked. We went downstairs and told Palmer we could not find the book. He said, “Oh, it will be found somewhere; I will go with you and look myself.” He did not go, but went out of the house, and I did not see him afterwards. I cannot say how long Palmer was in the room on the Thursday. There was no reason why we did not search the drawers for the betting book. There were some people in the room with Mr. Cook’s corpse, nailing the coffin, and they stood at the side of the drawers. Cross-examined by Mr. Serjeant Shee—Shortly after Cook refused to take the broth, saying he was too sick, Palmer came over and said, “He
- 51. L. Barnes must have it.” Did he say why he must have it?—No. Did he say anything to the effect, “Why, he has eaten nothing for several days”?—I cannot remember that he did. Did he ask whether anything had been eaten by him?—Not of me. You know, in fact, that Mr. Cook had had no substantial food?—He had some coffee and cocoa, and something like that. You say that on the Monday evening you saw Palmer between eight and nine o’clock going upstairs. Are you sure it was before nine o’clock?—I am not quite certain. Are you sure it was before half-past nine o’clock?—No, I did not pay particular attention to what the time was. Are you quite sure it was before ten o’clock?—Yes, I knew he had been to London. Did you know what hour the train came back from London?—I did not. An omnibus goes from the hotel to the station, starting from the hotel about half-past seven. It is not one mile from the station. I can give no notion of what time the express train comes into Rugeley from London, nor do I know if it stops at Rugeley. Do you persist that it must have been before ten o’clock that you saw Palmer come in?—I think it was. May it not have been a quarter past ten o’clock? You can easily have been mistaken about an hour; are you quite certain it was before ten o’clock?—I cannot remember now. You have stated that when Palmer left on the Monday evening he gave Cook something to drink in a glass; he snapped at the glass, and you said, “I cannot remember who gave it to him”; did you see the glass in Mr. Cook’s hands?—I cannot remember whether I saw the glass in Cook’s hands. Did you see his hand up to the glass?—I think I did. I think it was as if he was going to catch hold of it, but somebody else was holding it. Did you see the hand touch the glass?—I cannot remember that. I remember some one was holding it for him. Might he not be holding it too?—He might.
- 52. Anne Rowley C. Hawley Sarah Bond Anne Rowley, examined by Mr. Welsby—I live at Rugeley, and have been employed by Mr. Palmer as charwoman. On the Saturday before Mr. Cook died I remember being sent by Palmer to Mr. Robinson, of the Albion, for a little broth for Mr. Cook. The Albion is an inn in Rugeley, and a small distance from the Talbot Arms. I brought the broth, which was not warm, to Palmer’s house and put it by the fire. I left it at the fire and went back to my work in the kitchen. When the broth was hot Mr. Palmer brought it to me in the back kitchen. He poured it into a cup, which I held while he did so. He told me to take it across to the Talbot Arms for Mr. Cook, and to say to whoever I gave it to to ask Mr. Cook if he would take a little bread or a little toast with it, and to say that Mr. Smith had sent it. I took it to the Talbot Arms. He did not say why I was to say Mr. Smith had sent it. Mr. Jeremiah Smith is an attorney in Rugeley. He goes under the name of Jerry Smith, and is a friend of Palmer. I gave the broth to Lavinia Barnes. Cross-examined by Mr. Serjeant Shee—Mr. Smith was in the habit of putting up at the Albion, and took his meals there a good deal. He was intimate with Mr. Cook. I have not known them to dine together, but Mr. Cook was to have dined at Mr. Smith’s that day, but was unable to do so. The time between the broth being brought in to me and the time it was taken to the Talbot Arms would be about five minutes. Charles Hawley, examined by Mr. Bodkin—I am a gardener in Rugeley, and was occasionally employed by the prisoner in that capacity. I was in his house on the Sunday before Mr. Cook died, between twelve and one, and Mr. Palmer asked me whether I would take some broth to Mr. Cook. He gave me some broth in a small cup with a cover, and told me to take it over to the Talbot Arms. I gave it to one of the servant girls, either Mills or Lavinia Barnes. I cannot tell whether the broth was hot or not. Sarah Bond, examined by Mr. Huddleston—I was housekeeper at the Talbot Arms in November last. I saw Mr. Cook on the Thursday after he returned from Shrewsbury Races. I heard him say he was very poorly. About eight o’clock on Sunday evening I
- 53. Sarah Bond saw him in bed. He said he had been very ill, but was better. Soon after I came into the room I saw the prisoner. I asked what he thought about Mr. Cook, and he told me he was better. On the Saturday night I spoke to him about the advisability of having some one to be with Mr. Cook during the night. He said that either he or Jerry Smith would be there. I also spoke to him about it on the Sunday night, but he said that Cook was so much better he would not require any one. He would be much better without it. I asked him if Daniel Jenkins, the boots, should not sleep in the room, but he said he would much rather not. On Monday morning, a little before seven, he came into the kitchen to me. He said Cook was better, and asked me to make a cup of coffee for him. I made the coffee. He remained in the kitchen while I was making it, and took it from me to give to Mr. Cook. He said he was going to London that day, and he had asked Mr. Jones to come to be with Cook while he was away. Between eleven and twelve on Monday night the waitress came and told me that Mr. Cook was very ill. I went up to his room. There was no one with him. He was sitting up a little on the bed, and seemed disappointed when I came in that it was not Palmer. He said it was Mr. Palmer he wanted. I did not remain in the room above two or three minutes. I did not go downstairs, but remained on the landing, and was still there when Mr. Palmer came. I could see into the room from where I was standing. Palmer went into the room, and I heard he was giving him some pills. He then came out to fetch some medicine, and was not many minutes away before he came back. After he returned, I heard Mr. Cook was very sick and very ill. He told Mr. Palmer he thought he should die, and he must not leave him. Mr. Palmer came out again, and I asked him if Cook had any relatives. He said he had only a stepfather. I saw Cook on Tuesday, between three and four, when Mr. Jones came. I took him a little jelly shortly after six. He seemed very anxious for it, and said if he did not have something he thought he should die. He seemed a little better. I did not see him again alive. Cross-examined by Mr. Grove—I did not see Palmer on the Monday evening until a little before twelve. The last train, which stops at Rugeley at eight o’clock, is not an express train. The express does not stop at Rugeley, and passengers coming by the express have to take some conveyance from Stafford. I cannot say when they would arrive in the ordinary course. On the Monday night when I went up to Cook’s room he seemed disappointed that it was not Mr. Palmer. He seemed
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