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This review addresses potential applications of SPIONs in vitro (formulations), ex vivo (in biological
cells and tissues) and in vivo (preclinical animal models), as well as potential biomedical applications
in the context of drug targeting, disease treatment and therapeutic efficacy, and safety studies. The
reason why there seems to be no observed correlation between the net charge of adsorbed proteins
and the surface properties of the IONPs is likely due to the complexity of protein structure. Dextran
based shells, which are neutral, usually present low uptake 2,21 and require modifications for
efficient cellular internalisation. They are generally highly water-soluble, biodegradable and
inexpensive. Journal of Cardiovascular Development and Disease (JCDD). Within this context,
IONPs bear great potential for use in nanosystems capable of overcoming the physical barriers of the
microbial biofilm matrix in delivering the drugs directly to the target. Finally, a set of considerations
is made on IONPs toxicological aspects, as well as advances on coating strategies to elaborate more
biocompatible nanosystems. 2. Synthesis of IONPs There are three main routes for the synthesis of
IONPs: chemical, physical and biological. We use cookies on our website to ensure you get the best
experience. Life after death for empty shells: Crustacean fisheries create a mountain of waste shells,
made of a strong natural polymer, chitin. Despite the remarkable advantages of IONPs coating, some
divergences have been reported in the literature. Journal of Functional Morphology and Kinesiology
(JFMK). The efficiency of contrast agents in decreasing the relaxation time of surrounding protons is
normally expressed in terms of their relaxivity, defined as r 1 and r 2 for longitudinal and transverse
relaxivity, respectively. However to be used for stem cell labelling, the synthesised IONPs need to be
transferred to water. However, the data presented in the literature are sometimes conflicting, with
groups working on the development of IONPs often purporting the safety of their formulations,
whereas a smaller, but increasing, number of independent studies report specific toxicities. 17 The
use of IONPs as a contrast agent for organ imaging differs from its use for stem cell labelling. To
fully exploit the potential of these materials as contrast agents, there is still a need for a greater
understanding of how they react to physiological conditions. However, as wide variations have been
reported among different research protocols, a direct comparison of the results obtained cannot be
done. As we have discussed here, the protein corona that forms during labelling is influenced by
both the charge and coating of the IONP. Labelled stem cells, on the other hand, usually present
intracellular iron concentrations in the range of 3 to 30 pg per cell. Different endocytic mechanisms
have been suggested to be involved in IONP internalisation by cells, but there is no clear established
relationship between physicochemical properties and specific mechanisms of uptake. ISPRS
International Journal of Geo-Information (IJGI). Use of IONPs for any cell labelling and tracking
application requires a hydrophilic coating to make the particles stable in aqueous solutions. Find
support for a specific problem in the support section of our website. Oxidised proteins tend to
denature, making them more susceptible to proteolysis. Feature papers are submitted upon individual
invitation or recommendation by the scientific editors and must receive. Conflicts of Interest The
authors declare no conflict of interest. However, the IONPs obtained are normally of a polydisperse
nature. Such agents are generally split into T 1 and T 2 categories: most commonly, T 1 contrast
agents contain a paramagnetic metal lanthanide complex that alters the longitudinal ( T 1 ) relaxation
times of surrounding water protons whilst T 2 agents, containing a superparamagnetic iron oxide
core less than 20 nm in diameter, 4 alter the transverse ( T 2 ) relaxation times of water protons. It is
regarded as a “stealthy” coating due to low uptake of PEG coated materials into most cell types and
long circulation time in the blood. This occurs via a reduction of ferric iron to ferrous iron ( eqn (4)
), followed by Fenton chemistry ( eqn (5) ). 31 As such, the formation of these radicals can be
catalysed at the surface of the IONPs, or via free iron ions released in the cell's cytoplasm. Drug
carriers have also been tested as alternatives to combat the resistance of oral biofilms to commercially
available drugs.
These studies highlighted the difficulty of predicting the structure of the protein corona, but they
have also demonstrated that the type and surface charge of polymer coated IONPs play a dominant
role in protein adsorption. For stem cell labelling, many research groups prefer to use the co-
precipitation procedure with a polymer stabiliser, which can render the particles hydrophilic, since
this is a one step process that can produce significant quantities of IONPs. Factors such as core size,
core composition, hydrodynamic diameter and the overall available surface area are also likely to
contribute to stability in a lysosomal environment. As IONPs can only be used as contrast agents for
cell tracking if they are internalised by cells, the cellular dose is most relevant for their evaluation. In
some cases, the coatings can be rendered hydrophilic through a reaction with a polymer before or
after covalent attachment to the iron oxide core. These and other IONPs limitations, such as
oxidation and cell toxicity, can be overcome by an adequate surface-coating, implying that the
success of a IONPs-based nanosystem is also directly related to the properties of the coating
material. When the polymers are in an aqueous environment and the pH of the solution is below the p
K a of the amine functional group, the amine will become protonated giving it an overall positive
charge. Factors inherent to nanosystems involving IONPs tend to directly interfere with their
toxicity. The strength of the grafting bond plays an important role as competitive interactions
between polymers and proteins, as well as incubation temperature, could result in the polymer being
detached from the IONP surface, which could have further implications on colloidal stability,
toxicity and observed MRI signal over time. Polymers are widely used as coatings for IONPs as
they can increase colloidal stability in hydrophilic conditions, as well as protect the iron oxide core
from degradation. Despite the growing body of evidence attesting their biomedical usefulness,
superparamagnetic IONPs are still in early stage of clinical investigation, with studies pointing out to
the need for their improvement prior to their commercialization. Besides presenting solubility in most
of common solvents, PLGA can take different shapes and sizes, and encapsulates molecules of all
sizes. One particular study focused on creating pullulan coated IONPs with different surface charges
and sizes and evaluating the effect this could have on the uptake into bone marrow-derived rat
mesenchymal stem cells (rMSCs). 39 To vary surface charge, pullulan was functionalised with
ethylenediamine to give the polymer a positive charge, and succinic anhydride was introduced to
give a negative charge to the polymer. The effect of particle size is less clear, with some studies
suggesting an optimal size around 50 nm for uptake, although the notion of an “optimal” size has
been challenged by some research groups. 20 What should always be monitored, however, is the
colloidal stability of the IONPs. Researchers have been able to work around this problem via
crosslinking the polysaccharide chains through crosslinkers such as epichlorohydrin for dextran and
glutaldehyde for chitosan. The low molecular weight PEI was reacted with a hydrophobic alkyl
chain, which allowed for stabilisation of clusters of pre-formed hydrophobic IONPs in water. In an
effort to understand more about how the coating type affects the fate of IONPs in living systems,
there are now more studies emerging focusing on the quantitative analysis of the protein corona that
forms around IONPs in cell culture medium. We will also give some perspective on the challenges
and limitations that remain for polymer coated IONPs as MRI contrast agents for stem cell tracking.
International Journal of Translational Medicine (IJTM). IONPs have been used as carriers of
anticancer, alternative, immunosuppressive, anticonvulsant, anti-inflammatory, antibiotic and
antifungal agents. 4.1. Anticancer Drugs One of the major challenges in cancer treatment is the
tolerance developed throughout the therapy, which reduces response to the medicament. Summary
of studies assessing the toxicity of iron oxide magnetic nanoparticles (IONPs) carried out between
2014 and 2018. This can range from several days to several months depending on the experimental
conditions and model organism. Note that from the first issue of 2016, this journal uses article
numbers instead of page numbers. Once exposed to cell culture medium, the hydrodynamic diameter
was found to increase significantly, up to 100 times for PEI-coated and around 30 times for
polyacrylic acid-coated IONPs. When IONPs are taken into consideration, the expression of dose is
a difficult issue as no agreement exists on the most appropriate approach, and most investigators
utilise the so called gravimetric doses. 18 Here, the most common example is the use of mass per
volume of culture medium (?g ml ?1 ). Depending on the physicochemical characteristics of the
IONPs, these measures of dose can be very different, which is in contrast to soluble chemicals where
it is assumed that the nominal media concentration is proportional to the cellular dose. Whilst the
chitosan particles did not affect the chondrogenic potential of hMSC, Resovist did, although it is not
clear if this was due to the IONP coating or the iron oxide core. We demonstrated that manipulating
the surface charge by varying the amine containing DEAE-dextran within the polymer coating can
give a degree of control over stem cell uptake. However, it is still not precisely clear if it is the
polymer coating that leads directly to uptake, or if it is the polymer and charge specific proteins that
are incorporated in the protein corona in cell culture medium during labelling. In turn, coating of
textile fibers of wound dressings with patchouli essential oil-attached IONPs was effective in
reducing the number of S.
Again, these labeling procedures were shown to not affect viability or the differentiation potential of
the cells. 39. Journal of Low Power Electronics and Applications (JLPEA). Furthermore, the surface
charge of IONPs may affect cell cytotoxicity and genotoxicity. Colloidal stability in serum is not
absolutely essential, although it is desirable if one wants to understand interactions of IONPs with
stem cells based on surface properties rather than induced by gravitational forces (sedimentation). It
is therefore important that the size and zeta potential of the IONPs are assessed following incubation
in cell culture medium. Additionally, it is well accepted that the acidic environment (pH ? 4.5) of the
lysosomes might result in at least partial dissolution of IONPs with time, 6,28 resulting in iron ions
being leached from the particles. An important aspect of using stem cells in regenerative therapies is
the ability of scientists and clinicians to image them once they are administered to an organism,
allowing the tracking of their localisation within the body. Such agents are generally split into T 1
and T 2 categories: most commonly, T 1 contrast agents contain a paramagnetic metal lanthanide
complex that alters the longitudinal ( T 1 ) relaxation times of surrounding water protons whilst T 2
agents, containing a superparamagnetic iron oxide core less than 20 nm in diameter, 4 alter the
transverse ( T 2 ) relaxation times of water protons. For example, the versatility of RAFT was
demonstrated by synthesising three PEG based block co-polymers with different grafting groups:
phosphonic acid, carboxylic acid and glycerol ( Fig. 3c and 4 ). 15 The three polymers were used to
synthesise SPIONs in a co-precipitation approach using various polymer to iron salt ratios whilst
keeping the concentration of the iron salts the same for every reaction. Finally, a set of
considerations is made on IONPs toxicological aspects, as well as advances on coating strategies to
elaborate more biocompatible nanosystems. 2. Synthesis of IONPs There are three main routes for
the synthesis of IONPs: chemical, physical and biological. Thus, it is imperative to provide this
information when performing a comparative assessment of different polymer shells for MRI tracking.
Some of the functional groups that can be introduced are: amine, carboxylic acid, vinyl, and thiol.
13,14 Attachment of silica-based stabilisers can sometimes result in loss of colloidal stability in
water. However, this is not enough and the assessment of stem cell health should include
investigations on proliferation and migration capacity, the preservation of specific surface markers,
differentiation potential (“potency”) and functionality of the stem cell and its derivatives as well as
whether the labelled cells can induce any immunogenic response. Arias, L.S.; Pessan, J.P.; Vieira,
A.P.M.; Lima, T.M.T.d.; Delbem, A.C.B.; Monteiro, D.R. Using relatively low molecular weight PEI
(2 kDa) has been shown to improve biocompatibility. Coating with polymers and essential oils can
also reduce the toxic effects of IONPs. Journal of Pharmaceutical and BioTech Industry (JPBI).
Cellular uptake of SPIO can be exploited in a variety of potential clinical applications, including
stem cell and inflammation cell tracking and intra-cellular drug delivery to cancerous cells which
offers higher intra-cellular concentration. Gout, Urate, and Crystal Deposition Disease (GUCDD).
The region containing the administered cells ( e.g. right kidney) is detectable due to an increase in
negative contrast caused by changes in the relaxation times of surrounding protons as caused by the
presence of IONPs. The particles were then coated with PDMAAm by polymerising ( N, N -
dimethylacrylamide) in the presence of bare maghemite particles using free radical polymerisation.
Clinical translation, however, involves a good understanding of the regulatory pathways that
although not covered here, can be assessed in a recent review of the subject. 51. Find support for a
specific problem in the support section of our website. The degradation of IONPs can be quantified
using citrate containing buffers at pH 4.5. Although it does not exactly mimic a lysosomal
environment, this can be a useful tool for comparing the stability of different iron oxide cores. 2 For
example, the use of small molecules such as citrate 28 and 2,3-dimercaptosuccinic acid 29 as
coatings appear to lead to a lower stability when compared to the use of polymers. Interestingly, we
also showed that magnetophoretic mobility of cells ( Fig. 6b ) could be used as an accurate proxy
for predicting the resultant MRI contrast of stem cells after labelling, as it is sensitive to both uptake
and magnetisation of individual cells ( Fig. 6c and d ). 21. Polymers are often preferred to small
molecules as coatings as they can provide both colloidal stability and sufficient protection of the iron
oxide core at physiological pH. These and other IONPs limitations, such as oxidation and cell
toxicity, can be overcome by an adequate surface-coating, implying that the success of a IONPs-
based nanosystem is also directly related to the properties of the coating material. The authors
demonstrated that the release profile of NYS in a physical mixture of these isolated compounds
lasted about 20 min, compared to 1800 min of the IONPs-CS-NYS nanosystem. In fact, the first co-
precipitation of IONPs utilised dextran. 36 Chitosan is another polysaccharide polymer used for
coating IONPs. Summary of studies assessing the toxicity of iron oxide magnetic nanoparticles
(IONPs) carried out between 2014 and 2018.