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 Nanotechnology
Therapeutic, Nutraceutical, and
Cosmetic Advances
 Nanotechnology
Therapeutic, Nutraceutical, and
Cosmetic Advances

Edited by
Bhaskar Mazumder, Subhabrata Ray, Paulami Pal,
and Yashwant Pathak
CRC Press
Taylor & Francis Group
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Contents

Editors....................................................................................................................................................... vii
Contributors............................................................................................................................................... ix

1 Potential of Nanostructures for Drug Delivery: With a Special Reference to Polymeric

Nanoparticles..................................................................................................................................... 1
Pranab Jyoti Das, Laldusanga Pachuau, Ramkrishna Sen, and Bhaskar Mazumder

2 Characterization Techniques of Nanoparticles Applied in Drug

Delivery Systems.............................................................................................................................. 25
Vipin Kumar Sharma and Daphisha Marbaniang

3 Therapeutic Nanostructures in Antitubercular Therapy........................................................... 57

Paulami Pal, Subhabrata Ray, Anup Kumar Das, and Bhaskar Mazumder

4 Therapeutic Nanostructures for Improved Wound Healing...................................................... 75

Lalduhsanga Pachuau, Pranab Jyoti Das, and Bhaskar Mazumder

5 The Role of Nanotechnology in the Treatment of Drug Resistance Cancer............................. 95

Sandipan Dasgupta, Anup Kumar Das, Paulami Pal, Subhabrata Ray,
and Bhaskar Mazumder

6 Nanoemulsions in Non-Invasive Drug Delivery Systems.......................................................... 137

Ratna Jyoti Das, Subhabrata Ray, Paulami Pal, Anup Kumar Das,
and Bhaskar Mazumder

7 Nanostructures for Improving the Oral Bioavailability of Herbal Medicines........................ 173

Lalduhsanga Pachuau

8 Nanotechnology for Tissue Regeneration................................................................................... 197

Kumud Joshi, Pronobesh Chattopadhyay, and Bhaskar Mazumdar

9 Nanotechnology in Preventive and Emergency Healthcare...................................................... 221

Nilutpal Sharma Bora, Bhaskar Mazumder, Manash Pratim Pathak, Kumud Joshi, and
Pronobesh Chattopadhyay

10 Prospects of Nanotechnology in Brain Targeting Drug Delivery............................................ 273

Srijita Chakrabarti, Probin Kr Roy, Pronobesh Chattopadhyay, and Bhaskar Mazumder

11 Recent Advances and Potential Applications of Nanoemulsions in Food Stuffs:

Industrial Perspectives................................................................................................................. 315
Bankim Chandra Nandy, Pranab Jyoti Das, and Sandipan Dasgupta

12 Toxic Effects of Metal and Metal Oxide Nanoparticles on Humans

and the Environment.................................................................................................................... 345
Sanjay Dey, Bhaskar Mazumder, and Supriya Datta

v
vi Contents

13 Functional Foods and Nutraceuticals: An Overview of the Clinical Outcomes

and Evidence-Based Archive........................................................................................................ 373
Manjir Sarma Kataki, Ananya Rajkumari, and Bibhuti Bhusan Kakoti

14 Emulsification Technology for Cosmetics Preparation............................................................. 401

Kazi Asraf Ali and Sanjit Roy

15 Nanotechnology in Cosmetics: Safety Evaluation and Assessment......................................... 419

Sanjoy Kumar Das, Rajan Rajabalaya, and Sheba Rani N. David

Index....................................................................................................................................................... 447
Editors

Yashwant Pathak holds a Doctor of Philosophy (PhD) in Pharmaceutical Technology from Nagpur
University, India and an Executive Master of Business Administration (EMBA) and a Master of Science
(MS) in Conflict Management from Sullivan University. He is Professor and Associate Dean for Faculty
Affairs at the College of Pharmacy, University of South Florida, Tampa, Florida. With extensive expe-
rience in academia as well as industry, he has more than 100 publications, two patents and two patent
applications, and 21 edited books published, including seven books in nanotechnology and six in nutra-
ceuticals and drug delivery systems. He has published several books on cultural studies and conflict
management. He has received several National and International awards. Dr Yashwant Pathak is also an
Adjunct Professor at the College of Public Health, Airlangga University, Surabaya, Indonesia.

Bhaskar Mazumder , M. Pharm, PhD, FIC, Professor in the Department of Pharmaceutical Sciences,
Dibrugarh University, Assam, is a former Overseas Associate in the University of South Florida (Health).
He is a former visiting fellow of the Department of Pharmaceutical Sciences, Assam University, Assam,
India. He has more than 90 publications and 11 book chapters. He has nearly eight years of Industrial
experience in Formulation and Development in various companies and more than twenty years of experi-
ence in academic and research.

Subhabrata Ray , Principal, Dr. B. C. Roy College of Pharmacy and AHS Durgapur, WB has more than
eighteen years of Research and teaching experience. He completed B. Pharm (Hons) and M. Pharm (1st
Class) from Jadavpur University in 1996 and 1998 respectively. He was awarded Doctor in Philosophy
(PhD) in Pharmacy from Jadavpur University in year 2003. His field of Research Work is QSPR applica-
tions in Novel Drug Delivery Systems.

Paulami Pal is the Principal Investigator of projects sponsored under Women Scientist Scheme-A by
the Department of Science & Technology, Govt. of India and she is conducting her research work in the
Department of Pharmaceutical Sciences at Dibrugarh University, Assam, India. With more than two
years of teaching experience, her research interest lies in the field of developing novel drug delivery
systems with special attention to non-invasive drug delivery.

vii
Contributors

Kazi Asraf Ali Ratna Jyoti Das

Dr. B.C. Roy College of Pharmacy and Allied Department of Pharmaceutical Sciences
Health Sciences Dibrugarh University
Durgapur, India Dibrugarh, India

Nilutpal Sharma Bora Sanjoy Kumar Das

Division of Pharmaceutical Technology Institute of Pharmacy, Jalpaiguri
Defence Research Laboratory Government of West Bengal
Tezpur, India Jalpaiguri, India
and Sandipan Dasgupta
Department of Pharmacy
Department of Pharmaceutical Sciences
NSHM Knowledge Campus
Dibrugarh University
Kolkata Group of Institutions
Dibrugarh, India
Kolkata, India
Srijita Chakrabarti and
Division of Pharmaceutical Technology
Department of Pharmaceutical Sciences
Defence Research Laboratory
Dibrugarh University
Tezpur, India
Dibrugarh, India
and
Supriya Datta
Department of Pharmaceutical Sciences Bengal College of Pharmaceutical Sciences
Dibrugarh University and Research
Dibrugarh, India Durgapur, India

Pronobesh Chattopadhyay Sheba Rani N. David

Division of Pharmaceutical Technology PAPRSB Institute of Health Sciences
Defence Research Laboratory Universiti Brunei Darussalam
Tezpur, India Brunei Darussalam

Anup Kumar Das Sanjay Dey

Konark Herbals and Health Care Department of Pharmacy
Nani Daman, India Techno India University
Kolkata, India
and
Kumud Joshi
Department of Pharmaceutical Technology
Division of Pharmaceutical Technology
Adamas University
Defence Research Laboratory
Barasat, India
Tezpur, India
Pranab Joyti Das and
Department of Pharmaceutical Sciences
Department of Pharmaceutical Sciences
Assam University
Dibrugarh University
Assam, India
Dibrugarh, India
and
Bibhuti Bhusan Kakoti
Department of Pharmaceutical Sciences Department of Pharmaceutical Sciences
Dibrugarh University Dibrugarh University
Dibrugarh, India Dibrugarh, India

ix
x Contributors

Manjir Sarma Kataki Probin Kr Roy

Department of Pharmaceutical Sciences Division of Pharmaceutical Technology
Dibrugarh University Defence Research Laboratory
Dibrugarh, India Tezpur, India

Daphisha Marbaniang Rajan Rajabalaya

Department of Pharmaceutical Sciences PAPRSB Institute of Health Sciences
Dibrugarh University Universiti Brunei Darussalam
Dibrugarh, India Brunei Darussalam
Bhaskar Mazumder Ananya Rajkumari
Department of Pharmaceutical Sciences Department of Pharmaceutical Sciences
Dibrugarh University Dibrugarh University
Dibrugarh, India Dibrugarh, India
Bankim Chandra Nandy
Subhabrata Ray
Department of Pharmacy
Dr. B.C. Roy College of Pharmacy and Allied
Techno India University
Health Sciences
Kolkata, India
Durgapur, India
Lalduhsanga Pachuau
Department of Pharmaceutical Sciences Sanjit Roy
Assam University Department of Pharmaceutical Technology
Silchar, India Jadavpur University
Kolkata, India
Paulami Pal
Department of Pharmaceutical Sciences Ramkrishna Sen
Dibrugarh University Infectious Diseases and Immunology Division
Dibrugarh, India C.S.I.R.: Indian Institute of Chemical Biology
Kolkata, India
Yashwant Pathak
College of Pharmacy Vipin Kumar Sharma
University of South Florida Department of Pharmaceutical Sciences
Tampa Bay, Florida Faculty of Medical Science and Health
and Gurukul Kangri Vishwavidyalaya
Haridwar, India
Faculty of Public Health
Airlangga University
Surabaya, Indonesia

Manash Pratim Pathak

Division of Pharmaceutical Technology
Defence Research Laboratory
Tezpur, India
and
Department of Pharmaceutical Sciences
Dibrugarh University
Dibrugarh, India
1
Potential of Nanostructures for Drug Delivery: With
a Special Reference to Polymeric Nanoparticles

Pranab Jyoti Das, Laldusanga Pachuau, Ramkrishna Sen, and Bhaskar Mazumder

CONTENTS
1.1 Introduction....................................................................................................................................... 2
1.2 Various Nanostructures for Drug Delivery....................................................................................... 3
1.2.1 Nanoliposomes..................................................................................................................... 3
1.2.2 Polymersomes....................................................................................................................... 4
1.2.3 Dendrimers........................................................................................................................... 6
1.2.4 Cyclodextrin Inclusion Complex.......................................................................................... 8
1.2.5 Micelles................................................................................................................................ 8
1.2.6 Protein Nanoparticles........................................................................................................... 9
1.2.7 Biological Nanoparticles...................................................................................................... 9
1.2.8 Inorganic Nanoparticles....................................................................................................... 9
1.2.9 Hybrid Nanoparticles......................................................................................................... 10
1.2.10 Viral Nanoparticles............................................................................................................ 10
1.2.10.1 Advantages of Viral Nanoparticles as Drug Delivery Carriers...........................11
1.2.11 Fullerenes and Nanotubes...................................................................................................11
1.2.12 Quantum Dots.....................................................................................................................11
1.2.13 Carbon Nanotubes.............................................................................................................. 12
1.2.14 Solid Lipid Nanoparticles (SLNp)...................................................................................... 12
1.3 Polymeric Nanoparticles for Drug Delivery................................................................................... 13
1.3.1 Polymeric Nanoparticles for Targeted Therapy..................................................................14
1.3.1.1 Passive Targeting.................................................................................................14
1.3.1.2 Active Targeting...................................................................................................14
1.3.2 Multifunctional Polymeric Nanoparticles...........................................................................16
1.3.2.1 Simple Multiple Functionality of Polymeric Nanoparticles................................17
1.3.2.2 Complex Multiple Functionality of Nanoparticles..............................................17
1.4 Challenges for Nanoparticle-Based Drug Delivery.........................................................................17
1.5 Future Aspects of Nano-Size Drug Delivery Systems................................................................... 19
1.6 Conclusion....................................................................................................................................... 19
References................................................................................................................................................. 19

ABSTRACT: The impact of nanomaterials on drug delivery is significant and the emergence of poly-
meric nanoparticles provides a unique platform for the delivery of drug molecules of a diverse nature.
The conventional drug delivery system is widely changing with the development of nanoparticulate drug
delivery systems. Because of their unique physicochemical properties, nanomaterials can be used for the
strategic development of new drug delivery systems and reformulating existing drugs and therapeutics
to escalate the effectiveness, patent protection, patient compliance, and safety of drugs. Nanoscale drug
delivery systems such as nanoparticles, nanoliposome, nanoemulsions, nanosuspensions, dendrimers,
nanopores, nanotubes, nanocrystals, quantum dots, and nanosponge are believed to have the potential

1
2 Nanotechnology

to revolutionize the drug delivery strategy. Nanocarriers can be conjugated with a ligand such as an
antibody to favor a targeted therapeutic approach. In the present chapter we will mainly highlight the
current status of the nanoscale drug delivery systems along with the progress of research in the field.
Furthermore, we will throw some light on the development of polymeric nanoparticles and how multi-
functionality can be engineered into polymeric nanoparticles for tumor specific treatment. In short, we
will provide an update on how nanotherapeutics may revolutionize the entire drug therapy strategy and
bring it to a new look in the near future.

KEY WORDS: Nanostructures, polymeric nanoparticles, drug delivery, polymer, nanoscale

1.1 Introduction
Nanotechnology is a revolutionary area of science and technology which involves the creation and uti-
lization of materials, devices, or systems on the nanometer scale. Mathematically a nanometer is equal
to one thousand millionth of a meter. Nanotechnology is sparking innovation and plays a crucial role in
various biomedical applications, especially in drug delivery. Delivering a therapeutic compound to the
target site is a major problem in the treatment of many diseases. The conventional application of drugs
is characterized by limited effectiveness, poor biodistribution, and lack of selectivity. These limitations
and drawbacks can be overcome by controlling drug delivery (Wilczewska et al., 2012). In the past three
decades, the explosive development of nanotechnology has been considered to be revolutionizing devel-
opment in the field of drug targeting. The systems are exploited for therapeutic function to take the drug
in the body in a controlled manner from the site of administration to the therapeutic target. Accumulation
of therapeutic compounds in the target site increases and, consequently, the required doses of drugs
are lower. Cancer stands out as a disease most likely to benefit from targeted drug delivery. Tumor
cells express many molecules on their surface that distinguish them from normal cells. Therefore,
nanoparticles have been considered as appropriate vehicles to provide an ideal platform for personalized
approaches to cancer diagnosis and therapy in cancer disease management (Ruoslahti et al., 2010).
Advances in nanotechnology that enable drugs to preserve their efficacy while being delivered to pre-
cise therapeutic targets are creating a host of opportunities for drug developers. In addition, by combin-
ing nanotechnology-based, target-specific drug therapy with methods for early diagnosis of pathologies,
we are getting closer to creating the ultimate functional drug carrier. Many researchers attach ethylene
glycol molecules to nanoparticles that deliver therapeutic drugs to cancer tumors. The ethylene glycol
molecules stop white blood cells from recognizing the nanoparticles as foreign materials, allowing them
to circulate in the blood stream long enough to attach to cancer tumors. Researchers are also continuing
to look for more effective methods to target nanoparticles carrying therapeutic drugs directly to diseased
cells by using two types of nanoparticles. The first type of nanoparticle locates the cancer tumor and the
second type of nanoparticle (carrying the therapeutic drugs) hones in on a signal generated by the first
type of nanoparticle. Other researchers are using a photosensitizing agent to enhance the ability of drug
carrying nanoparticles to enter tumors. First, they let the photosensitizing agent accumulate in the tumor,
then illuminate the tumor with infrared light. The photosensitizing agent causes the blood vessels in the
tumor to be more porous, therefore more drug-carrying nanoparticles can enter the tumor. One research
group has found that a disk-shaped nanoparticle (nanodisk) will stick to the surface of a tumor longer
than a spherical-shaped nanoparticle, providing more efficient transfer of therapeutic drugs to the tumor.
Another group of researchers have found that rod-shaped nanoparticles are more effective at delivering
chemotherapy drugs to breast cancer cells than spherical nanoparticles. Thus, the pharmaceutical scien-
tists are attracted towards newer, novel nanoscale drug delivery systems for various reasons. The most
important reason is that due to the increase in number of surface atoms or molecules to the total number
of atoms or molecules, the surface area increases and thus helps in improving drug delivery strategies.
This in turn helps to bind, adsorb, and allow passage of other bioactive compounds such as drugs, probes,
and proteins. Sometimes the drug particle itself can be engineered to form nanoscale-size materials too
(Hadjipanayis et al., 2010). Due to their unique size (smaller than eukaryotic or prokaryotic cells) nano-
materials can eventually reach generally inaccessible areas, such as cancer cells, inflamed tissues, etc.,
Potential of Nanostructures for Drug Delivery 3

in much higher amounts due to their enhanced permeability and retention effect (EPR) and can impair
lymphatic drainage. Thus, this unique principle can be used for the administration of genes and proteins
through the peroral route of administration (De Jong and Borm, 2008).
Safety is an important matter in the proper use of nanomaterials in drug delivery. Nanomaterials used
for drug delivery should be easily soluble, safe, and biocompatible, as well as bioavailable at the site of
treatment. They should not block blood vessels and should be less invasive. The toxicity associated with
the nanomaterials for drug delivery should be negligible so that such material can be used to target the
specific diseased tissue in a safe concentration (Webster et al., 2013). Nanomaterials help protect from
the degradation of drug substances (both enzymatic as well as hydrolytic) in the gastrointestinal environ-
ment and they also help in bypassing “fast-pass” metabolism in the liver. The nanoscale drug delivery
strategy increases the circulation time, especially those coated with hydrophilic polymers, and is hence
suitable for increasing the efficacy of bioactives with short half-lives. This principle is again utilized by
the formulation scientist for sustained release of drug molecules from nanomaterials, as well as for the
delivery of deoxyribonucleic acid (DNA) (Chakroborty et al., 2013). The mass transfer rate of the drug
to the biological fluid is enhanced, onset of therapeutic action is prolonged, and thus the therapeutic dose
as well as dosing frequency is reduced. The premature loss of drug substances through rapid clearance,
opsonization, and macrophageal uptake and metabolism can also be prevented (Sahoo et al., 2007).
Nanomaterials also increase retention and accumulation due to their bio-adhesion property.
Thus, the nanoscale drug delivery vehicles have shown their uniqueness in encapsulating a wide range
of bioactives such as small molecules (hydrophilic and/or hydrophobic), peptides, protein-based drugs, and
nucleic acids. By encapsulating or attaching these molecules inside or on the surface of a nanocarrier, the
solubility and stability of the drugs can be improved, providing an opportunity to reevaluate some potential
drugs which were previously ignored because of their poor pharmacokinetics (Langer, 1998). Encapsulated
or surface-adhered molecules can be released from nanocarriers in a controlled manner for a prolonged
time to maintain a drug concentration within a therapeutic window or the release can be triggered by
some stimulus unique to the delivery site (Moghimi, 2006). Nanomaterials can also be engineered to be
multifunctional with the ability to target diseased tissue, carry imaging agents for detection, and deliver
multiple therapeutic agents for combination therapy (Nasongkla et al., 2006). The multifunctionality of
nanomaterial-based delivery systems offer the opportunity to develop novel approaches to deliver drugs
that may result in alternative or complementary therapeutic options for the treatment of disease.
Nanoscale drug delivery systems such as nanoparticles, nanoliposomes, dendrimers, fullerenes, nano-
pores, nanotubes, nanoshells, quantum dots, nanocapsules, nanospheres, nanovaccines, nanocrystals,
etc., are believed to have the potential to revolutionize drug delivery systems. Furthermore, nanomateri-
als on chips, nanorobotics, magnetic nanoparticles attached to specific antibodies, nano-sized empty
virus capsids, and magnetic immunoassay are new dimensions for their use in drug delivery. Thus,
nanomaterials can be used for the strategic development of new drug delivery systems and for reformu-
lating existing drugs to enhance their effectiveness, patent protection, patient compliance, and safety,
decreasing the cost of health care (Couvreur, 2013).
In this chapter we will mainly focus on therapeutic nanostructures with a particular emphasis on the
development of nanocarrier drug delivery systems. We will also throw some light on polymeric nanopar-
ticles and their various applications in novel drug delivery.

1.2 Various Nanostructures for Drug Delivery

The diversity of delivery system, as discussed hereunder, allows nanomaterials to be developed with
a diverse array of shapes, sizes, and surface properties that enables them to be tailored for specific
applications.

1.2.1 Nanoliposomes
The nano-sized vesicle made up of a phospholipid membrane, generally unilamellar, with an aqueous
interior is known as a nanoliposome. Hydrophilic molecules can be encapsulated in the inner core while
4 Nanotechnology

hydrophobic molecules can be carried in the hydrophobic domains of the lipid bilayer. Physicochemical
properties of liposomes can be precisely modified to control surface charge, functionality, and size by
simply mixing commercially available lipid molecules. The United States Food and Drug Administration
(FDA) approved lipids used for the preparation of liposomal vesicles are 1,2-d​istea​royl-s​n-gly​cero-​3-pho​
sphoe​thano​lamin​e (DSPE), hydrogenated phosphatidylcholine from soybean lecithin (HSPC), egg yolk
phosphatidylglycerol (EggPG), and 1,2-distearoyl-glycero-3-phosphocholine (DSPC), etc. Among all
other techniques, the thin film hydration technique is the most suitable and feasible for the preparation of
nanoliposomes. Lipid vesicles have been investigated as carriers for anticancers, antifungals, analgesics,
and gene therapies, as well as for vaccine delivery (Lian and Ho, 2001). Surface functionalization is also
possible to produce stealth liposomes – liposomes that avoid Mononuclear Phagocyte System (MPS)
uptake, thus having increased circulation times (Mufamadi et al., 2011). Polyethylene glycol (PEG),
chitosan, silk-fibroin, and polyvinyl alcohol (PVA), etc., are generally used for surface functionalization
and to avoid opsonization of the lipid vesicles. Targeted nanoliposomal drug delivery is more efficacious
than the non-targeted drug delivery systems. The C6-ceremide ligand-induced nanoliposome used to
treat blood cancer directly targets the over-expressed leukemic cells and decreases the high expression
of survivin proteins in those leukemic cells. The future avenues that can be exploited using lipid vesicle
platforms include association with imaging or tracing elements to track the fate of nanoliposomes in
vivo, co-delivery of synergistic elements, and association of bio-responsive elements such as temperature
sensitive elements or pH sensitive elements. Thus, liposome technologies are expected to bring lots of
change in sophisticated drug delivery methods. A sample of literature indicating generalized advantages
and disadvantages and the variety of ways liposomal formulations are currently being used is highlighted
in Table 1.1.
Wang et al. (2015) successfully developed the dual-ligand liposomes modified with the specific ligand
T7 motif and non-specific TAT. This liposomal delivery system possessed increased cellular uptake
efficiency and targeting specificity in A549 cells, whose transferrin receptor (TFR) expression levels
were high, and achieved an efficient, synergistic, targeted delivery of payload into tumor cells in A549
tumor-bearing nude mice, ultimately achieving excellent therapeutic efficacy on tumor-bearing mice.
The findings of this study suggest that the T7- and TAT-modified liposomes are a potential antitumor
drug delivery system (Wang et al., 2015). Li et al. (2015) developed PEGylated vinorelbine (VRB) plus
quinacrine cationic liposomes for treating non-small cell lung cancer (NSCLC). The PEGylated VRB
plus quinacrine cationic liposomes were able to increase cellular uptake and accumulate in the A549
cells. Furthermore, they exhibited significant inhibitory effects to A549 cells, and showed the stron-
gest effects on inhibiting vasculogenic mimicry (VM) channels. In addition, studies on tumor-bearing
mice confirmed that the PEGylated VRB plus quinacrine cationic liposomes did show an enhanced
anticancer efficacy. Action mechanisms showed that the enhanced efficacies in treating NSCLC were
related to activate apoptotic enzymes (caspases 9 and 3), pro-apoptotic proteins (Bax), and tumor sup-
pressor genes (P53), and to suppress anti-apoptotic proteins (Bcl-2 and Mcl-1) (Li et al., 2015). Qu et
al. (2014) formulated docetaxel (DTX) and BCL-2 small interfering ribonucleic acid (siRNA) incorpo-
rated PEGylated liposomes to systemically deliver in a lung cancer model (A549). The lipo-DTX/siRNA
exhibited sustained-release kinetics, effectively inhibited cell proliferation (A549 and H226) and modi-
fied cell apoptosis and cell cycle analysis. An in vivo antitumor study on an A549 cell-bearing xenograft
tumor model exhibited a remarkable tumor regression profile for lipo-DTX/siRNA with a 100% survival
rate. The favorable tumor inhibition response was attributed to the synergistic effect of DTX potency
and the multidrug resistance (MDR) reversing ability of siRNA in the tumor mass. Their unique findings
support the hypothesis that siRNA treatment combined with a classical anticancer drug could represent
a new approach in the treatment of lung cancer with MDR (Qu et al., 2014).

1.2.2 Polymersomes
Polymersomes are polymeric, tiny, hollow spheres that enclose a solution. They are amphiphilic block
copolymers, forming a shell that can encapsulate aqueous-soluble compounds inside the aqueous core
and entrap organic-soluble components within the shell itself. Although liposomes also work on the
same principle, polymersomes have advantages over liposomes, with a longer half-life (20–30 hours) and
TABLE 1.1
Liposomal Nanostructures
General
Advantages
1. Research is well
established
2. Surface charge can be
modified to improve
circulation and cellular
adhesion and uptake
General Component Target Outcome of
Disadvantages Loaded Size Moieties Research References
1. Tend to be more siRNA 150 nm Sigma receptor Develop a new drug release mechanism for targeted Li et al. (2010)
water permeable expressing cancer siRNA delivery (LCP (Liposome/Calcium/Phosphate)
2. Have a low cells (anisamide) core calcium phosphate dissolved in endosome
circulation time causing swelling and endosomal rupture to delivery
siRNA to cytosol)
Potential of Nanostructures for Drug Delivery
DOX 147 nm Targeted release via Evaluation of DOX-loaded liposome lipid gas-filled Lentacker et al.
localized ultrasound microbubble system as an anticancer therapeutic (2010)
exposure delivery system (complex was more effective at
reducing cancer cell viability than free DOX or
DOX-loaded liposomes, cavitation and implosion of
microbubbles may enhance DOX uptake)
ITZ (Intraconazol) 264.5 nm No active targeting Biodistribution of ITZ-loaded liposomes (ITZ-loaded Tang et al.
liposomes produced longer circulation half-life as well (2010)
as greater ITZ levels in the liver and spleen than
current commercial formulations)
Calcein and 46.43 nm Antibody KN2/NRY Stealth liposomes modified to recognize CD163 as a Etzerodt et al.
doxorubicin or human potential way to target drugs to macrophages (2012)
haptoglobin
5
6 Nanotechnology

increased stability, for practical applications (Discher et al., 1999). Polymersomes are used for loading
and protecting sensitive molecules, such as drugs, enzymes, other proteins and peptides, and DNA and
RNA fragments. The polymersome membrane provides a physical barrier that isolates the encapsulated
material from external materials, such as those found in biological systems. The term “polymersome”
for vesicles made from block copolymers was coined in 1999. The use of synthetic polymers enables
researchers to modify the physicochemical characteristics of the membrane and thus control permeabil-
ity, release rates, stability, and other properties of the polymersome. There are many techniques available
that can be used to prepare polymersomes by self-assembly of amphiphilic block copolymers. Typical
methods are polymer rehydration techniques, which are based on the hydration of amphiphilic block
copolymer films to induce self-assembly. Other important preparation methods are solvent-switching
techniques. Lomas et al. (2007) have investigated the encapsulation of plasmid DNA by a biocompatible,
pH-sensitive block copolymer poly(2-(methacryloyloxy)ethyl phosp​horyl​choli​ne-co​-poly​(2-(d​iisop​ropyl​
amino​)ethy​l methacrylate) (PMPC-PDPA), polymersome formation, and delivery of the DNA-copolymer
complex to the cell cytosol.
Polymersomes can also encapsulate diagnostic payloads. To date, polymersomes have been used in
optical imaging, magnetic resonance imaging (MRI), and ultrasound imaging. By using polymersomes,
useful information can be extended to obtain higher resolution and monitor biological pathways and
cellular functions in vivo. The surface charge density plays a key role in the biodistribution and phar-
macokinetics of polymersomes. Interactions with the opsonins can be reduced by the introduction of a
slightly negative or positive charge on the surface of the polymersomes, yielding prolonged blood circu-
lation times. Polymersomes based on poly(ethylene glycol)-b-poly(D,L-lactide) (PEG-PDLLA) with zeta
potentials (−7.6 to −38.7 mV) were investigated for the effect of surface charge on blood circulation time
and tissue distribution in tumor-bearing mice. PEG-PDLLA polymersomes with a low zeta potential
(−7.6 mV) and a diameter of approximately 100 nm had a much longer half-life time and a reduced liver
uptake (28% injected dose (ID) after 3 days) as compared to stealth liposomes (Lee et al., 2011). This
implied that the charge density of anionic polymersomes effects circulation kinetics and biodistribution
and showed that polymersomes with a slightly negative surface charge are most suited for in vivo admin-
istration. Table 1.2 highlights the properties and application of copolymers forming polymersomes.

1.2.3 Dendrimers
Dendrimers are branched polymers, resembling the structure of a tree. These nanostructured macromol-
ecules show their potential abilities in entrapping and/or conjugating the high molecular weight hydro-
philic as well as hydrophobic entities by host–guest interactions and covalent bonding respectively. They
are in high demand because of their defined structure and versatility in drug delivery. Since Vogtle first
used them in 1978, dendrimers have provided a novel, and one of the most efficient, nanotechnology
platform for drug delivery (Buhleier et al., 1978). They are three-dimensional, branched, well-organized,
nanoscopic macromolecules (typically 5,000–500,000 g/mol), possess a low polydispersity index, and
are gaining more importance in the emerging field of nanomedicine. The name is actually derived from

TABLE 1.2
Properties and Application of Copolymers Forming Polymersomes

Copolymer Properties Application

Poly(ethylene oxide)-polystyrene
Poly(acrylic acid)-polystyrene
Poly(ethylene oxide)-poly(butadiene)
Poly(ethylene oxide)-poly(butylene oxide)
Poly(2 vinylpyridine)-poly(ethylene oxide)
Ability to form large compound
vesicular aggregates
Ability to form large compound
vesicular aggregates
Mechanical toughness, biological
inertness, crosslink ability
Selective permeability
pH sensitivity
Potential use in controlled
release, biomedical applications
Potential drug delivery vector
NIR (Near-infrared) imaging
contrast agent
Drug delivery
Controlled release
18 Nanotechnology

experimental therapeutics for lung cancer utilize different approaches, balancing the design with
targeting and imaging moieties and anticancer agents. It is expected that the current research work
efforts in nanomedicine will continue to move towards safe, efficient, and feasible drug delivery, and
highly sensitive and improved imaging agents for diagnostic and disease monitoring applications.
However, nanomedicine research is facing a lot of challenges during the development of novel ideas
and in translating them into clinical practice. Particle size distribution, structure, biocompatibil-
ity, and surface chemistry are the possible risk factors in the biological environment. A number of
obstacles including immune reaction, efficiency in targeting, rate of clearance from circulation, and
ability to cross biological barriers will follow when these nanoparticle systems enter the preclinical
and clinical testing arenas. It is very difficult to determine the particle–particle interaction within a
biological environment and the intracellular trafficking of nanoparticles. Particle sizes of more than
500 nm are not recommended for IV administration because these particles are rapidly eliminated
from circulation. Particle sizes of less than 200 nm with a spherical shape and smooth texture can be
easily transported through tumor vasculature and into tumor cells. Such physical characteristics are
favorable to nanoparticles in utilizing the EPR effect associated with solid tumors. In lung cancer,
the EPR effect plays an important role in determining the efficacy of the nanoparticle-based drug
delivery system (Babu et al., 2013). Moreover, the poor lymphatic flows in the tumor tissue are advan-
tageous to this EPR effect and result in enhanced retention of nanoparticles within the tumor site.
Particle–particle interactions and aggregation tendencies are mostly dependent on the zeta potential
of the nanoparticles. Positively charged nanoparticles have an increased affinity for the negatively
charged cellular membranes of all cells in the body. Poor stability of nanoparticle systems has been
attributed to their aggregation tendencies in the physiological environment. Once aggregated, it is
almost impossible to redisperse the particles into their original distribution pattern; while shear
forces can be used to redisperse the particles, this may affect the drug loading and therapeutic
efficiencies.
Nanotoxicology research has shown that the interactions between nanomaterials and cells, animals,
humans, and the environment are remarkably complex. As a matter of interest, increased scientific
contributions to the field of nanomedicine have resulted in the emergence of a new area of research:
nanotoxicology (Hubbs et al., 2011). Even nanoparticles having strong therapeutic properties towards
various types of cancer in preclinical studies carry the risk of inducing toxicity to normal cells. Here
mentioned are some inorganic and metal-based nanoparticles that induce toxicity to normal cells. In
the past few years, several studies have investigated the toxic effects of silica nanoparticles in vitro
and in vivo. For example, Napierska et al. (2009) observed that 15 nm silica nanoparticles could cause
cytotoxic damage and decrease cell survival in human endothelial cells, McCarthy et al. (2012) found
that silica nanoparticles in their amorphous state have the potential to cause inflammatory reactions in
target organs resulting in apoptotic cell death, and Chang et al. (2007) observed that high dosages of
silica nanoparticles induce cell membrane damage. Therefore, the use of silica-based nanoparticles for
cancer therapy is limited to low concentrations (0.1 mg/mL) in vitro. There is still limited knowledge
about the effects of silica nanoparticles on tumor cells. The toxicity of titanium oxide (TiO2) nanopar-
ticles towards healthy cells is also a matter of concern considering its biological applications (Trouiller
et al., 2009). Research evidence suggests that TiO2 nanoparticles may possess higher toxicity potential
than their bulk materials (Long et al., 2007; Magaye et al., 2012; Zhao et al., 2009). Zhao et al. (2009)
found that TiO2 nanoparticles caused higher cytotoxicity than fine particles in cell culture. Due to their
very small size, nanoparticles can penetrate basic biological structures, which may, in turn, disrupt their
normal function (Buzea et al., 2007; Zhao et al., 2009). Li et al. (2008) observed that the erythrocytes
treated with TiO2 nanoparticles underwent abnormal sedimentation, hemagglutination, and hemolysis,
which was totally different from those treated with TiO2 fine particles. Carbon nanotubes have also
been reported to exhibit toxicity to normal cells. Muller et al. (2008) and Ye et al. (2009) reported
similar findings with SWNTs on the proliferation of A549 lung cancer cells and rat lung epithelial cells
respectively. Carbon nanotubes upon interaction with live cells generate reactive oxygen species causing
mitochondrial dysfunction and lipid peroxidation (Manke et al., 2013). Therefore, stringent in vitro and
in vivo toxicity studies for each of the novel nanoparticle systems must be conducted to ensure safety
prior to their application in humans.
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 INDEX
Abortion caused by lead, 35
Absorption of lead: cutaneous, 25; from lung, 23; gastric, 19;
intestinal, 21, 22; in liver, 24; mechanism of, 20; prevention
of, from stomach, 23
Accumulators. See Electric accumulators
Acetate of lead, poisoning by, 94
Acetic acid, solvent action of, on lead oxide, 15
Acid lemonade, 185
Acidity, gastric contents, 15
Action of lead: on gold and silver, 3; on water, 3
Acute encephalopathy, 54, 95
Acute lead poisoning, 110, 111
Acute nephritis, 60, 131
Aerographing, 272, 280
Ætiology of lead poisoning, 7
Age as affecting lead poisoning, 35, 239
Akremnin soap, 238
Albuminate of lead, preparation of, 17
Albuminuria, 128
Albuminuric retinitis, 160
Alcohol: as predisposing cause, 37, 64; gastritis and plumbism,
64; in experimental poisoning, 85; similar effect to lead on
kidney, 131
Alteration in blood-corpuscles in lead anæmia, 133
Alternation of employment, 34, 251
Amaurosis, 70, 160
Amblyopia, 76
Amenorrhœa, 36
Anæmia, 39, 112, 132, 136, 227; treatment of, 190
Anemometers, 219
Antibrachial paralysis, 144, 148
Antimony, effect of, on lead fume, 199
Appointed surgeon, 112, 221
Aran-Duchenne paralysis, 149
Armit, nickel poisoning, 11
Arsenic: Cloetta’s experiments, 24; excretion of, in fæces, 24
Arterio-sclerosis, 116
Arthralgia, 50, 161
Arthritis, 40
Artificial gastric juice, action of, 17
Atrophic nerve changes, 69
Attack rate from lead poisoning (table), 55
Autopsy, points to be noted in, 162
Bacup epidemic, 4
Basophile granules, 77, 133, 135, 179
Baths, 238
Blood: action of lead salts on, 2; in lead poisoning, 70, 78, 134,
179; pressure, 116, 180; vessels, 68, 70, 75
Blue line, 122, 123, 128, 226; experimental production of, 41,
124; from diachylon, 13
Brachial paralysis, 148
Brain, analysis of, 96
Brass, presence of lead in, 263
Brassworkers and plumbism, 51, 263
Breathing experiments, 81
Bright’s disease and lead poisoning, 60
Burtonian line. See Blue line
Carbon in lung, 11
Card system, use of, 186
Central nervous system, 69, 157; treatment, 196
Cerebral symptoms, 51, 157
Certifying surgeons, reports of, 45, 221
Chandelier fitters, poisoning among, 264
Channels of lead absorption, 8
Chemical analysis of brain, 95
Chemical characters of lead salts, 4
Chemical diagnosis, 166
Chemical examination of organs, 163
Chemistry of lead, 2
Choroidal atrophy, 161
Chromate of lead in yarn-dyeing, 298
Chrome colours, 287
Chronic colic, 119
Circulatory system, 75, 137
Cirrhosis of kidney, 74
Coach-painting, 288; dust in atmosphere breathed, 205;
leadless paints, 290; reported cases from, 289; sandpapering
in, 289
Colic, 116, 117, 118, 119, 188, 190; differential diagnosis, 188;
treatment of, 187
Colloidal lead, 5
Colon, palpation of, 126
Colours, 285
Comparative mortality, 59
Conjunctiva in lead anæmia, 132
Constipation, 115
Copper extraction, plumbism in, 246
Cutaneous absorption, 25
Death certificates in plumbism, 57
Degeneration of blood vessels, 68
Determination of lead in urine, 169
Diachylon, 13
Diagnosis: from chemical analysis, 166; of lead colic, 120, 188
Diarrhœa, 115
Differential count in lead anæmia, 134, 137, 180
Digestion experiments, 16, 17
Drink for lead-workers, 186
Drugs in lead colic, 189
Duration of employment and plumbism, 52
Dust, lead: amount of, in air breathed, 199, 207; chief cause of
plumbism, 10; “laying,” difficulties of, 11; rate of settling, 7;
respirators for, 207
Dysmenorrhœa, 36
Earthenware: and china, 270; attack rate, 56; decorative
processes, 272; dust in atmosphere, 204, 206; glaze
processes, 272; leadless glaze, 274; low solubility glaze, 274;
Potteries Committee on, recommendations of, 275; reported
cases in (table), 271
Electric accumulators, 281; reported plumbism in, 283;
ventilation in, 216
Electrical reactions, 151, 153, 154
Electrical treatment, 194
Electro-chemical tests, 168
Electrolytic estimation of lead, 174; reactions, 5
Enamelling (vitreous), 278; aerographing in, 280; use of
leadless colours in, 278
Encephalitis, case of chronic, 71
Encephalopathy, 54, 68, 71, 157
Estimation of lead: in digestion, difficulties of, 18; in urine, 169,
170, 175
Excretion: of arsenic, 24; of lead salts, 32, 127, 128
Excretory system, 72
Exhaust ventilation. See Ventilation
Experimental lead poisoning: pathology of, 81; post-mortem
findings, 91; symptoms, 69, 89, 103
Experimental arsenic poisoning, 24
Experimental results, summary, 104
Eye changes, 76, 150, 158
Facial nerve, paralysis of, 195
Fæces: examination for lead in, 182; lead in, 32, 64
Family susceptibility, 30
Fans. See Ventilation
Faradism for paralysis, 195
File-cutting, 256; atrophy of muscles in, 52, 257; reported cases
in, 258
File-hardening, 258; lead fume from, 200, 201; use of fused
metallic salts for, 258
Forms of paralysis, 54, 142
Fritted lead: action of water on, 89; poisoning, 34, 97; solubility
test, 14
Fume (lead) in atmosphere breathed, 198, 207
Gastric absorption, 19, 21, 22
Gastric digestion, artificial, 17
Gastric juice, action on lead salts, 15, 16
Gastritis in plumbism, 65
Gastro-intestinal absorption, 12, 13, 64
Generalized paralysis, 151
Glass-cutting, 283
Glaze, 272; leadless, 274; low solubility, 274
Gout, 38
Hæmatoporphyrin, 180, 182
Hæmoglobin, 113, 132
Hæmorrhages in plumbism, 76
Hæmostatic action of lead salts, 2
Hair lotions, poisoning from, 13
Harness furniture, tinning of, 259
Headache, 120
Health Register, 228
Heart, 139, 193
Heart symptoms, 193
Heat, exhaust by, 208
Histological examination of lead tissues, 163, 176
Histology: of experimental poisoning, 92; of nervous system, 67
House-painting, 291; regulations for, 293; reported plumbism in,
291
Hunter, John, “dry bellyache” from rum, 1
Hyperæsthesia, 161
Immunity, 27, 29, 113
Incipient symptoms, 112, 222
India-rubber, manufacture of, 301
Inhalation experiments (table), 101
Inoculation experiments, 83, 88, 99
Instruction of worker, 240
Interstitial nephritis, 130
Intestinal absorption, 22, 94
Intestinal staining, 21, 94, 125
Iodine in plumbism, 192
Ionization in paralysis, 195
Iron drums, tinning of, 260
Italians and lead poisoning, 30
Kidney: changes, 73, 74, 129; excretion of lead by, 128;
interstitial hæmorrhages, 130
Lactic acid, solvent action of, 15
Large intestine and lead absorption, 21
Lavatories, 235, 238
Lead: compounds, 7; fume and dust in atmosphere, 198-207; in
urine, 129, 167; melting-point, 2, 199
Lead bed in file-cutting, 257
Lead burning, 262; in electric accumulators, 283
Lead chloride in tinning, 200
Lead dust: minimal toxic dose, 31, 207; rate of settling, 7; size
of particles, 12
Lead fume in tinning, 202
Lead oxide, danger from skimming, 200
Lead piping, 251
Lead poisoning: acute, 110; mortality, 57; entry of poison, 8
Lead silicate, 34
Lead smelting: and silver refining, 242; analysis of fumes in,
246; cupellation process, 246; Huntingdon-Heberlein
process, 243; in blast furnace, 243; Parkes’s process, 244;
Pattinson process, 245; reported plumbism, 248
Leadless glaze, 274
Leadless paints, 291
Lead salts: action on blood, 2; action of gastric juice on, 16, 17
Lemonade, sulphuric acid, 185
Letterpress printing. See Printing
Litharge, manufacture of, 250
Lithopone, 291, 292
Litho-transfers, 277
Liver, absorption by, 24
Loss of fat in plumbism, 112
Lumbago, 115, 192
Lung: absorption by, 98; phagocytic absorption of lead, 23
Meal-rooms, requirements of, 234
Mechanism of lead absorption, 20
Medical examination, periodical, 115, 221-229
Medical Health Register, 228
Medical practitioners and notification, 44
Melting-point of lead, 2, 199
Menorrhagia, 36
Mental symptoms, 114, 121, 158
Metallic capsules, 297
Metallic taste, 127
Micro-chemical tests, 167
Molten lead, contact with, 297
Mortality figures, 59
Motor-cars. See Coach-painting
Muscles paralyzed in experimental poisoning, 144
Muscular system, affections of, 114-161
Nephritis, 192
Nervous symptoms, 66, 67, 140; treatment, 193
Neuritis, peripheral, 66, 67
Nickel carbonyl poisoning via lung, 11
Normal lead, 33
Notification of plumbism, 44
Œdema of brain, 159
Olive oil in colic, 189
Ophthalmoscopic examination, 160
Oral sepsis, 38
Orange chrome, 299
Organic mixtures, lead in, 173
Organic compounds of lead, 5
Organs of generation, effect on, 36
Overalls and head coverings, 230
Oxides of lead, 3, 249
Painters and lead poisoning, 107 See also House-painting
Paints: and colours, manufacture of, 285; leadless, 29, 291
Pancreatic digestion, action of, 17
Paralysis: in animals, 14; electrical reactions in, 181; forms of,
64, 66, 142; general, 151; in file-cutters, 152; insidious onset
of, 114; of special sense organs, 150; prognosis of, 197;
statistics of, 53
Parotitis, 127
Pathology of lead poisoning, 62
“Pentarcomb” exhaust, 217, 254
Peptonate of lead, 18
Peptone, solvent action of, 19
Perambulators, painting of, 290
Perihepatitis, 264
Peripheral neuritis, 266
Peritonitis, saturnine, 65
Peroneal paralysis, 149
Phagocytosis of lead particles, 20
Phthisis: in printing, 256; not a sequela, 60
Physiology of digestion, 16
Plumbing, 261
Plumbism, reported cases (1900-1909), 46, 47
Plumbo-solvency of water, 4
Porcelain enamelling, 278
Post-mortem signs, 91, 161
Potassium iodide, action of, 32, 191
Pottery. See Earthenware
Predisposing causes, 36, 42
Presaturnine state, 184
Preventive measures: age of employment, 239; baths, 238;
cloakroom, 231; exhaust ventilation, 207; floors, 240; food,
86; head coverings, 231; instruction of worker, 240; meal-
room, 234; overalls, 230; periodical examination, 221;
separation of processes, 239; washing accommodation, 235
Printing: compositors’ work, 255; linotype machine, 200, 211,
217, 253; reported cases from, 252; stereo-casting, 254;
type-casting, 252
Prodromal symptoms: of colic, 118; of paralysis, 141
Prognosis in lead poisoning, 197
Progressive spinal muscular atrophy, 68
Pulse-rate, alteration of, 76, 115, 118
Purgatives in lead colic, 188
Putty powder, 283
Pyorrhœa alveolaris as predisposing cause, 40, 124
Qualitative tests, 166
Quantitative estimation of lead, 170
Reactions of degeneration, 152
Red lead: manufacture of, 249; reported attacks in, 249
Relative toxic dose of lead compounds, 105
Repairs in factory as cause of plumbism, 10
Respirators, inefficiency of, 217
Respiratory absorption, 9
Rheumatic pains, 121, 161, 192
Safes, painting of, 290
Salivary glands and excretion of lead, 125
“Selective” action of lead on nerves, 147
Sequelæ of lead poisoning, 57, 60
Sex as affecting susceptibility, 35
Sheet lead, 241
Shipbuilding, 295; reported plumbism, 295
Shot-making, 298
Silicates of lead, 34
Silver refining. See Lead smelting
Size of particles of lead compounds, 12, 34
Skin, colour of, 132
Smelting of lead. See Lead smelting
Solar plexus, 65
Soldering, 261
Solubility: of lead salts, 5, 15, 16, 17; test for fritted lead, 14
Solvent action of peptone, 19
Spastic paraplegia, 68
Spiegeleisen, poisoning in manufacture of, 246
Spring tempering, fume from, 201, 296
Stained-glass painting, 285
Statistics of plumbism, 44, 45
Susceptibility, 27
Tape measures, painting of, 290
Tea lead, 251
Temperature in lead poisoning, 118
Tempering files, 200
Terne plates, 260
Tests for lead, 167
Tetramethyl diphenyl test, 169
Thorpe test, 275
Tiles. See Earthenware
Tinning: of hollow-ware, 259; of harness furniture, 259; of
irondrums, 260; dust in, 203; lead chloride fume in, 202-203;
repeated attacks in, 261
Tolerance of lead, 28, 113
Toxic dose: of lead acetate, 110; of lead carbonate, 110; of lead
dust, 31, 207; of fritted lead dust, 88, 97; of white-lead dust,
85
Treatment of acute lead poisoning, 111, 184
Tremor, 142, 156
Turpentine poisoning, experimental, 108
Type metal, 202
Urine: acidity, 181; chemical examination of, 180; determination
of lead in, 167; lead in, 32, 73, 169; phosphates, 181
Vaso-motor changes, 65, 76, 140
Ventilation (exhaust), 207-220; by fans, 210; by heat, 208;
composing boxes, 255; essential points, 208; in earthenware,
273; in electric accumulators, 216, 282; in enamelling, 278; in
glass-cutting, 284; in india-rubber, 302; in lead smelting, 245;
in litharge, 251; in paints, 215, 286; in printing foundry, 254; in
 red lead, 250; in spelter, 249; in tinning, 259; in vacuum
cleaning, 218; in white lead, 214, 268; in yarn-heading, 300;
smoke-test, 218
Volatility of lead, 2
Washing accommodation, 235
Wasting in lead poisoning, 113, 115, 145
Water, action on lead, 3, 4
White lead: Brimsdown process, 269; casual labour in, 269;
cause of dangers in, 266; chamber process, 268; diminution
in reported cases, 270; Dutch process, 265; precipitation
process, 269; ventilation in, 214
Works’ medicines, 185
Wrist-drop. See Paralysis
Yarn-dyeing with chromate of lead, 298
Zinc: action on kidney, 130; paints, 292, 294

BILLING AND SONS, LTD., PRINTERS, GUILDFORD

 Transcriber’s Notes
The text used in this document is the one used in
the source document, except as mentioned below.
In particular, non-English words and phrases and
titles and author names of references, and
summations and other calculations in tables have
not been corrected, unless mentioned below.
Table numbering (or the lack thereof) has not
been standardised.
Depending on the hard- and software used to read
this text and their settings, not all elements may
display as intended.
Page 1, 6: Stockhusen is probably an error for
Stockhausen.
Page 38, the reference to Goadby[13] points to a
publication by Garrod.
Page 52: hyperthenar eminence may be an error for
hypothenar eminence.
Page 64, ... se recontrant d’une manière diffuse ...:
possibly an error for ... se rencontrant d’une
manière diffuse ....
Page 70, bottom row of Table IX: possibly the first
column should read Average age at death.
Page 220, Literature reference [5]: there is no
footnote marker in the text, and therefore no back-
link to the text.
Changes made
Tables and illustrations have been moved out of text
paragraphs. Some of the tables have been re-
arranged or split for legibility; ditto marks and the
word Ditto have in several places been replaced
with the dittoed text.
Some obvious minor typographical and punctuation
errors have been corrected silently.
Page 3: ... mascicot and litharge ... changed to ...
massicot and litharge ....
Page 47, Table III bottom part: value for 1911 in the
row Other industries changed from 8 to 88⁴
(based on the totals given).
Page 61, Footnote [2]: Dr. John Tathan changed to
Dr. John Tatham.
Page 75: Pfleuger changed to Pflueger.
Page 76: Seiffert changed to Seifert.
Page 79, references [16] and [27]: Bleilähnung
changed to Bleilähmung; reference [49]: les
Maladies du Pois et Reins changed to les
Maladies du Foie et des Reins.
Page 88: eutetic entangling changed to eutectic
entangling.
Page 151: Electrical Reactions. changed to
Electrical Reactions.
Page 169: magnese changed to manganese.
Page 220: Leclere de Pulligny changed to Leclerc
de Pulligny.
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