Perfluorocarbon Utilization for Oxygen Delivery to Cancerous Cells

Lawson Spence
May 2022
CHEM 0436
Dr. Rachael Day
Drury University

Abstract:
Perfluorocarbon materials are
compounds that, given the nature of the
molecule, are capable of carrying cargo once
loaded into nanoemulsions. The
nanoemulsions can be made and loaded with
cargo to be delivered throughout the body.
This characteristic gives perfluorocarbon
materials possible utility to be used for a
variety of uses and a possible alternative
way to deliver oxygen throughout the body
or to a localized area. Cancerous cells are
often hypoxic and inflamed and restoring
oxygen concentration to these affected areas
offers a promising method of enhancing
common therapeutic methods.
Keywords: Perfluorocarbon,
Nanoemulsions, Oxygen Delivery, Cancer,
Hypoxia, Inflammation
Introduction to Perfluorocarbons
& Cell Hypoxia
The fight against cancer is ongoing,
and many treatments in the clinic use
chemotherapeutics to promote cancer cell
death.1 These types of treatments fail to treat
the underlying hypoxia and inflammation
found in solid tumors.2 Hypoxia and
inflammation are linked at both the
molecular and the diseased levels resulting
in solid tumors that are resistant to
traditional chemotherapeutics. To induce an
inflammatory response cells can be treated
with varying concentrations
lipopolysaccharide at many time points. The
inflammation of the cells can also be
quantitatively analyzed by measuring the
levels of transcription factors HIF-1 and NF-
κB. Perfluorocarbons can then be utilized to
Spence 1
deliver oxygen to these hypoxic/inflamed
cells.
Perfluorocarbons have desirable
characteristics as synthetic oxygen carriers.
The compact size of PFC particles exhibit
20 times the solubility of gasses for water
and bind 40-50 times more oxygen than
hemoglobin.3 A dose of 2.7 g/kg of
perfluorooctyl bromide estimated to be
equivalent in carrying capacity to 4 g/dL of
hemoglobin. Perfluorocarbons were
discovered and developed in large quantities
in association with the manhattan project
during World War II.
Perfluorocarbons Utility in
Clinical Treatments
Perfluorocarbons have proved their
usefulness in various areas of clinical
treatments. The most well-known
characteristic of these materials is their
oxygen carrying capacity, which has
allowed for perfluorocarbons to be used as
an alternative blood supply for delivering
oxygen throughout the body.
Perfluorocarbons can also be used to
cool systems for semiconductor particle
detectors. Evaporative fluorocarbon is used
to cool semiconductor pixel and micro-strip
sensors at the CERN large hadron collider.4
In a study from Vacek, et. al, a sonar
instrument was used to measure sound
of
velocity in perfluorocarbon liquids and
irradiation studies were made to determine
how suitable the liquids were for use in the
large hadron collider’s high radiation
environment.
Perfluorocarbons have also been
used to enhance the performance of hepatic

cultures. In these cells, it is often difficult to
deliver oxygen within their three-
dimensional configurations. PFCs offer an
extraordinarily high oxygen carrying
capacity. A PFC oxygen carrier can be
added to significantly increase the oxygen
capacity in a medium.5 The work in this
study clarifies the benefits of using PFCs to
enhance the functional performance of
three-dimensional liver systems. This allows
for an example of utilizing these
perfluorocarbons to a more specific local
source, rather than producing systemic
oxygenation.
Perfluorocarbon liquids have been
used to facilitate surgery in a multitude of
conditions. More specifically, in
ophthalmology cases including: proliferative
vitreoretinopathy, giant retinal tears,
drainage of suprachoroidal hemorrhages,
diabetic traction, and more. The clarity of
PFC liquids, which have a refractive index
similar to water, allows the use of a normal
contact lens for vitreous surgery while the
low viscosity facilitates tissue manipulation,
injection, and removal.6 This study did find
that PFC liquids are not tolerated in the
anterior chamber of the eye, and often
caused a corneal edema within 2-3 days at
the site of contact. This shows our current
limitations while utilizing these
perfluorocarbon materials in clinical
therapeutic use. Understanding potential
consequences of PFC administration is vital
before the use of any therapeutic
methodologies.
Another specific case in the field of
ophthalmology, perfluorocarbon gasses can
be used in the treatment of retinal
detachment.7 Before this study, four PFC
chains had been studied in animals. This
Spence 2
study used these PFC gasses in 30 patients.
The larger volumes injected into patients
made for extended disappearance times. The
expansion potential of these PFC gasses was
estimated to be the same as was measured in
the animal model.
Using PFC nanoparticles enhances
oxygen levels and can also inhibit tumor
growth with its utilization in combination
with photodynamic therapy.8 Photodynamic
therapy (PDT) kills cancer cells by
converting tumor oxygen into reactive
singlet oxygen using a photosensitizer. In
tumors, pre-existing hypoxia and oxygen
consumption during PDT can hamper
photodynamic efficacy. To overcome this
problem, this study loads a photosensitizer
into perfluorocarbon nanodroplets. This
significantly enhances the effect of the
photosensitizer.
Stabilizing Perfluorocarbon
Nanoemulsions:
Stabilizing PFC nanoemulsions with
the use of polymer amphiphiles can be
achieved with varying methods. PFC
nanoemulsions are droplets of fluorous
solvent stabilized by surfactants dispersed in
water.2 The size, stability, and surface
chemistry of PFC nanoemulsions are
controlled by the surfactant that is used to
stabilize the nanoemulsions. Hydrophilic
block length and identity, the overall
polymer hydrophilic/lipophilic balance, and
the polymer architecture are all important
factors.2 Changing these allows for greater
control over the nanoemulsions specific
characteristics including size, stability,
payload retention, cellular internalization

and protein adsorption of the
perfluorocarbons.
One study from Mayes, et. al. uses
an acrylate polymer with PFC and
poly(oxyethylene) ester group to stabilize an
emulsion of functional monomer, cross-
linker, print molecule, initiator, and
porogenic solvent in a more atypical PFC
material, perfluoro(methylcyclohexane). UV
irradiation of this combination of polymer
and perfluorocarbon resulted in polymer
beads.9 These polymers gave the beaded
packings low back pressure and rapid
diffusion and good separation even at high
flow rates.
Figure 1)
Determining the amounts of
dissolved oxygen in perfluorocarbon
nanoemulsions is an important characteristic
to quantify when attempting to utilize PFC
as an alternative oxygen carrier. One method
of quantifying this internal oxygen
environment is studied from Fraker, C. A.
The study begins by reviewing how
quantification of the liquids characteristics
has previously relied on laboratory
equipment such as in-line gas
chromatography with temperature-controlled
Spence 3
glass diffusion cells. In the work done in this
study, an alternative method is used to
determine the oxygen content that has been
dissolved in PFC nanoemulsions. This
method implemented a stirred oxygen
consumption microchamber that goes along
with an enzymatic reaction for the
determination of oxygen by optical density
measurements.10 The oxygen consumption
from enzymatic processes is recorded along
with the oxygen depletion rates. The study
found a strong correlation between the
reaction rate and the total measured oxygen
concentrations.10
Perfluorocarbons (PFCs) for
Systemic Oxygen Delivery
Many different blood substitutes can
be used as an alternative method of
delivering oxygen throughout the body
when endogenous hemoglobin is
insufficient. Oxygen carriers that are used as
an alternative to endogenous blood can
facilitate oxygen delivery to tissues. Once
oxygen is delivered to specific tissues that
are relatively low in oxygen concentration
the oxygen carrier releases its oxygen into
the lower concentration through simple
diffusion. Alternative blood substitutes can
also be utilized to disperse gasses other than
oxygen systemically.11 The dissolution and
transport of nitrogen and other gasses
throughout the body is an important
characteristic of any load carrying blood
substitute and should be analyzed when
describing a compound's oxygen carrying
capacity.
Oxygen delivery has been
established in animal models and through
Phase II and III human clinical trials. 12
Multiple fluorocarbons have been
 Spence 4

investigated for use as oxygen carriers, creating the emulsions themselves. The
including lipophilic and “regular” PFCs. properties, preparation, composition and
Organ retention of PFCs is an exponential physiological assessment of PFC emulsions.
function of molecular weight. Fluorocarbons PFCs can have potentially therapeutic uses
containing lipophilic elements are excreted in liquid ventilation, treatment of
more rapidly than what would be predicted decompression sickness, organ perfusion,
of their molecular weight. Rapid excretion oxygenation of ischaemic and malignant
of the PFC requires a touch of lipid tissues, and as contrast media for NMR
solubility, meaning that the PFC should not imaging.14
be too heavy in terms of MW. On the other PFC nanomaterials as a useful
hand, emulsion stability requires low water material for enhancing photodynamic
solubility. Because of this, the selected PFC therapy (PDT).15 PDT is a treatment where a
to use should not be too light. When photosensitizer is irradiated with light. PDT
selecting a perfluorocarbon for use, the is often utilized in treating cancerous cells in
molecule should have relatively high lipid tumors. Cancerous cells are commonly
solubility and the lowest possible water hypoxic, and delivering these
solubility. These are two conditions that are photosensitizers along with oxygen to these
difficult to satisfy simultaneously. Vapor cells is desirable to return the cells to
pressure, which also depends on molecular normoxia.15
weight, is an important parameter. A PFC
that is too light can favor retention of air in
the alveoli, resulting in increased pulmonary
residual volume. In order to avoid this
phenomenon, the vapor pressure of the PFC
phase should not exceed about 10 torr.12
One further study also discusses key
issues related to the selection of an
appropriate, readily excretable PFC and the
engineering of a stable injectable PFC
emulsion.13 Oxygent (PFC emulsion made
primarily of F-octyl bromide) is efficacious
in avoiding and reducing red cell transfusion
during surgery. This study searches for
possible interactions between Oxygent and
fluids present during cardiopulmonary
bypass surgery and found no effect of the
emulsions on hemostasis, hemolysis and
blood rheology.13
Different PFC materials give varying
characteristics when their emulsion forms
are prepared, including varying methods of
 Spence 5

with compromised tissue oxygenation

(cerebral/myocardial ischaemia, air
embolism, emergency/trauma surgery) as
long as no allogeneic blood is available.17
The study also states the use of PFC
a)
b)
Common photosensitizers
Tumor inhibition from PDT utilization with
emulsions can augment tumor oxygenation
simultaneous PFC oxygen delivery utilization to render these tumor cells more sensitive to
(Figure 2)
radiation and chemotherapy. The study also
This review highlights
finds that the relatively short half-life of
benefits/limitations of several different
FPC emulsions (< 24 h) will not
nanomaterial structures for uses in
compromise their success in reducing the
photodynamic therapy.15 The study finds
requirement for allogeneic blood
that PDT with fluorous materials has a
transfusions. 17
promising future to treat diseases by
Research from Dr. Krafft at the
delivering oxygen and photosensitizers.
University of Strasbourg looks at methods of
Continued optimization is needed and could
reducing hypoxia in tumors with
possibly use mesoporous silica nanoparticles
perfluorocarbon-based oxygen carriers.
as molecular oxygen shuttles through the
Hypoxia of cancerous cells is a major
inclusion of fluorous solvents.15
problem when attempting various cancer
Perfluorocarbons can also be utilized
treatments.18 Most cancer treatments require
for lung ventilation in newborn children.
oxygen for the degradation of the tumor
PFCs not only provide effective gas
with reactive oxygen species.
exchange but also acid/base balance and
improve lung function. PFC ventilation has
been suggested as a therapy for severe
respiratory distress in human infants.16 The
purpose of this work was to determine the
optimal volumes of PFC to be delivered, the
frequency of the ventilatory cycle, the
oxygen flow rate and the best circuit set up
for neonatal application. The results showed
that total liquid ventilation is a valid
alternative to gas ventilation. Especially
when neonates with insufficient or no
production of surfactant are concerned.
PFCs can be specifically
interchanged as a blood substitute in order to
reduce allogeneic blood transfusions or to
improve tissue oxygenation.17 One study
also states that additional uses of PFC
emulsions can include treatments of diseases
 Spence 6

clinical use.19 Strategies to overcome these

failures will be presented along with
findings. Further research is needed to
develop strategies to counteract these
compounds’ shortcomings.

Potential PFC Utilization Side

Effects

The pharmacokinetics and side

(Figure 3) effects of PFC-based blood substitutes can
Liquid perfluorocarbons are solvents be analyzed to better understand potential
that allow to restore normal oxygen levels to unintended side effects with clinical
these hypoxic areas. Local oxygen delivery perfluorocarbon usage. In general, these
with the nanoemulsions occurs facilitated by molecules do not pose any toxicologic risk
ultrasound. The nanoemulsions can also be from metabolic degradation. Intravenous
loaded with alternative cargo that could aid PFC emulsions are cleared from the blood
in the cancer treatment process.18 These through a process involving phagocytosis by
emulsions can help store anything from macrophages and later elimination through
chemotherapeutics to photosensitizers. This the lungs during respiration.20
study concludes by finding that PFC-based
carriers may provide new strategies for
improving immune responses in cancer
patients.
Perfluoro-based oxygen carriers that
exhibit characteristics in their nanoemulsion
form that take advantage of high solubility
respiratory gasses. There are currently no
perfluorocarbon-based oxygen carriers
approved for clinical uses. Many of these
substances have attempted for approval but
failed due to secondary effects of the
surfactants employed, like Fluosol DA.19
Others, like Oxygent, were found to have Figure 4)
adverse cerebrovascular effects on Phagocytosis of PFC emulsion
cardiopulmonary bypass. One study from particles lead to normal biological effects
Castro and Barceno aims to review the most that are a consequence of a normal host-
common perfluorocarbons that are used for defense mechanism. Stimulation of
oxygen delivery and to reflect on their macrophages releases intracellular products
specific causes for failure to be approved for (metabolites of the arachidonic acid cascade

and cytokines).20 These products are
responsible for more of the biological effects
that come with PFC emulsion use
(cutaneous flushing, fever at lower doses,
and macrophage hypertrophy and
recruitment at higher doses. These effects do
not result in any permanent tissue alteration,
even with prolonged exposure at relatively
high doses. One study analyzing side effects
from PFC therapeutics finds that the
emulsions may elicit minor untoward
effects, but that these effects are reversible
and, at clinically relevant doses, do not pose
a toxicologic risk.20
Cancer Cells and their
Hypoxic/Inflamed
Characteristics
Cell death can occur from over-
immune system functioning. Immunogenic
cell death causes the release of tumor-
associated antigens and triggers other
immune cells to exhibit an anti-tumor
immune response. Immunogenic cell death-
inducing medicines exhibit a strong
potential for enhancing chemotherapy in
clinical applications.1 This review shows
nanoemulsions characteristics for mediating
an immune reaction during any
chemotherapeutic treatment in response to
cancer diagnosis.
Diminishing tumors’ hypoxic state
through the utilization of perfluorocarbon
oxygen carriers can be utilized along with
multiple other therapeutic remedies to treat a
cancer diagnosis. One study shows how
PFC-based oxygen carriers also increase the
lifetime of oxygen and can enhance
photodynamic therapy, along with
Spence 7
radiotherapy and chemotherapy.21 The use of
PFC nanocarriers also promote T cell
infiltration, which are an important aspect of
the bodys’ immune response towards
cancerous cells. Hypoxia is a major problem
for most cancer treatments that require
oxygen to generate reactive oxygen species
that destroy tumors.21 The local oxygen
delivery is facilitated by the use of
ultrasound. PFC nanocarriers can also be
loaded with fluorescent dyes,
photosensitizers, or loaded with
chemotherapeutics. Lastly, the study from
Dr. Krafft finds that perfluorocarbon
payload carriers could also provide new
ways to promote T-cell localization towards
tumors to return a greater and more specific
immune response.
Lipopolysaccharide Induced
Inflammation and Alternative
Methods
Lipopolysaccharide (LPS) can be
utilized in laboratory settings to induce an
inflammatory response to be analyzed and
treated. Varying levels of LPS can also
induce a spectrum of amounts of
inflammation. The purpose of a study from
Liang and Baudouin is to evaluate and
compare the effects of lipopolysaccharide.
Three rabbit corneal injury models are
utilized to make this comparison. Three
corneal models were tested, using corneal
incision, corneal epithelium scraping, and
corneal suture. Ten rabbits were used in
each model and divided into subgroups, with
or without LPS installation, where saline
was used for a control group. The study
found that LPS induced earlier and higher

levels of inflammation in eyes that were
subjected to scraping and suturing compared
to saline, showing that the LPS had induced
a larger amount of inflammation. 22 The
results indicated that LPS is a potent
proinflammatory stimulus and its exposure
has major effects on inflammation,
angiogenesis, and apoptosis.22
Multiple quantitative measurements
can be utilized to show varying levels of
intracellular inflammation. Analyzing
inflammation as a biological response of the
immune system is an important
characteristic to quantify any inflammatory
response. Inflammation can be triggered by
pathogens, cellular damage, and toxic
compounds. These can induce acute or
chronic inflammatory responses throughout
the body. Inflammatory signaling pathways
become activated during this time, most
commonly the NF-κB, MAPK, and JAK-
STAT pathways. One study reviews altering
inflammatory responses in various organs,
looking at organ-specific inflammatory
responses.23 The study also shows the NF-
κB pathway which is triggered by TLRs and
inflammatory cytokines, like TNF and IL-1.
NF-κB signaling also requires IKK subunits
that regulate the pathways activation
through IκB phosphorylation.23
Other studies have looked at the
inflammatory response in multiple cell
types. Cardiomyocytes can also be induced
to become inflamed and analyzed. In this
setting, cells were treated with
lipopolysaccharide (LPS) in varying
concentrations and times. It was found that
LPS inhibited conductance of calcium
activated potassium channels and also
enhanced sodium/calcium exchange
(antiporter). 24
The LPS also induced
Spence 8
prolonged action potential duration which
suggested electrical dysfunction in the
cellular environment. 24
Inflammatory Response in Cells
(Transcription Factor Activation)
HIF and NF-κB
The hypoxic environment stemming
from inflammation plays an important role
in many diseases. Mammals are seen to have
developed conserved programs of
transcriptional response to the hypoxic
environment, along with inflammation.25
Both of these characteristics commonly
occur together and transcription factors are
able to respond to these cellular
characteristics. A review discussing the
current understanding of the cellular
hypoxic response and inflammatory
transcription factors crosstalk analyzes the
present pathways in this cellular response.
One study specifically analyzes their
presence in rheumatoid arthritis,
inflammatory bowel disease and colorectal
cancer.25 It is also found that individuals
with mountain sickness have also presented
with increased levels of inflammatory
cytokines, specifically cytokine IL-6.25
An oxygen rich environment is
inherently necessary for aerobic life at the
cellular level. Aerobic life is dependent on
molecular oxygen for ATP regeneration
through oxidative phosphorylation. This is
only possible in a small range of oxygen
concentrations. Variations in this level of
oxygen are toxic and produce the generation
of reactive oxygen species (ROS).26 Cells
have been found to have developed
strategies to respond to changes in this

oxygen concentration. Specific transcription
factors are activated and target genes
become targeted. HIF-1 and NF-κB are
regulated and there is speculation on the
intracellular mechanism for the
determination of this change in oxygen
levels in the cellular environment.26
Inflammation was initially seen early
in human history and was characterized as
having features of rubor, tumor, calor, and
dolor. Modern scientific analyses have
allowed for us to see characteristics of
inflammation at the molecular level. As we
have already discussed, there are immediate
changes in intracellular transcription factor
activation, including HIF-1 and NF-κB.
Acute inflammation is also seen to trigger an
increased liver synthesis of positive acute-
phase proteins (APPs).27 The serum level of
these APPs later returns to a base
concentration when the factor that caused it
is no longer present. In clinical treatments of
an inflammatory patient, diagnoses are made
by analyzing specific markers such as
presence of these mentioned inflammatory
markers. Acute-phase C-reactive protein
(CRP) is a vital protein to include in an
assessment of any clinical inflammation as
its determination can be used as an
inflammatory biomarker in many diseases.27
One studies’ focus is determining the
mechanism that HIF-1 (hypoxia inducible
factor 1) is translated from gene activation
during any cellular hypoxic state. The
production of HIF-1 and NF-κB mediate the
cell's transcription response to a hypoxic
environment. A lack of HIF-1 production
has been found to be associated with
disorders such as chronic hypoxia from
pulmonary hypertension.28 A study from
BelAiba et. al. found that hypoxia did
Spence 9
indeed transiently elevate the production of
HIF-1 mRNA and was found to have the
maximum production at one hour after the
hypoxic event.28 The study found that
deletion of the HIF-1 promoter found the
region responsible for hypoxic induction.
Hypoxia induced nuclear translocation of
NF-κB subunits p50 and p65. Inhibition of
NF-κB diminished hypoxic induction of
HIF-1, mRNA, and later protein synthesis.
The study concludes that HIF-1 is a
transcriptional target of NF-κB which is
activated from a PI3 Kinase pathway under
hypoxic conditions.28
Macrophage concentration in
hypoxic areas and their reaction to hypoxia
are also key factors in understanding the
mechanisms of how hypoxia has an
influence on immunity. Data shows how the
hypoxic environment often creates
variations in macrophages phenotypes and
their overall plasticity.29 It was found that
hypoxia generated a regulated control of
macrophages phenotypic plasticity, and
further research will find new effective ways
to manage diseases with hypoxic
disturbances.
HIF-1 as a response to a hypoxic
environment is especially present in
malignant melanoma. HIF-1 consists of a
constitutive beta unit and the oxygen
responsive alpha subunit. This alpha subunit
is what is found to be the master activator of
the cellular transcriptional response to
hypoxia and what propagates the gene
expression that is induced during a hypoxic
cellular environment. Overexpression of this
protein is linked to a progression of many
tumor types (head/neck, cervical carcinoma,
leukemia, and renal cell carcinoma).30 This
study from Kuphal demonstrates that HIF-1
 Spence 10

activity is increased in malignant melanoma medicinal therapeutic treatments besides

cells that are also under normal oxygen systemic oxygen delivery. With the
concentrations. This effect is because of the continuous research in this field, it is likely
constitutive HIF-1 expression, which is the that the development of an efficacious
default pathway for transport and is an method of PFC utilization will be created
unregulated pathway. The inhibition of the and utilized in the near future.
NF-κB pathway lowered the intracellular
accumulation of HIF-1 and also suggests
that reactive oxygen species along with NF-
κB activity are responsible for this HIF-1
accumulation.30 This study concluded that
overproduction of HIF-1 in melanoma is
mediated by reactive oxygen species and the
NF-κB pathway. 30

Conclusion (more work needs to

be done/future of PFC use)

To utilize perfluorocarbons on a
regular basis, further work needs to be
completed. With hopes to use these as an
alternative method to deliver oxygen to cells
undergoing any sort of hypoxic event is a
therapeutic strategy that is still in the
beginning stages of development. First,
easily obtainable methods of creating
emulsions will need to be developed. Also
maintaining these emulsions for storage and
loading them with their specific cargo, in
this case oxygen, is another obstacle
preventing their widespread usage. Then,
determining methods of delivery in clinical
use and understanding the pharmacokinetics
will prove useful to eliminate any
unintended side effects.
These materials have also shown
promising characteristics for their usage in
other various clinical applications. These
materials’ inherent cargo carrying
capabilities could prove useful in other
 Spence 11

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