The application of nanoparticles in Selective Targeting of

stem cells, Differentiation and Monitoring of Stem Cells

based therapies
Patent Search Report

Submitted by

PRATHAP S
514BM6009

Department of Biotechnology & Medical Engineering

National Institute of Technology
Rourkela-769008, Orissa, India.

ABSTRACT
The stem cells based therapies are currently one of the most promising areas that will lead to
disease treatment and reparative medicine. But the problem in stem cell therapies is stem cell
targeting to the site of interest, differentiating into desired cell type and monitoring. But to
all these problems associated with stem cell therapies can be unfold using nanoparticles.
Nanoparticles have promising applications in the field of tissue engineering, drug delivery,
and bioimaging. Biocompatible magnetic nanoparticles mainly consist of a core of a
magnetite (Fe3O4) or magnetite (Fe2O3) core with biocompatible coating either a silica,
dextran, or PVA coating may be utilized. The functionalization of the coatings can be done
and cross-linked to membrane attachment motifs such that magnetic nanoparticle binding,
loading, and targeting stem cell can be done. The bone marrow-derived mesenchymal
stem cells have the ability to differentiate into osteogenic and chondrogenic lineage by the
specific receptors activation using magnetic nanoparticles. The lowering oxidative stress in
the stem cells increases the Stem cell growth and division rates. The stem cells proliferation
will facilitate the administration of cerium oxide nanoparticles as stem cells proliferation
requires an environment where oxidants are minimum. Hence, we can conclude that
nanoparticles and magnetic particles can be used to solve the problems associated with stem
cell-based therapies.
Keywords: Stem cell therapies, Magnetic nanoparticles, Metal nanoparticles,
Cerium oxide nanoparticles

List of Patent
SL No

Patent NO

Date of Patent

1.

US 8,772,032 B2

Jul. 8, 2014

2.

US 8,469,034 B2

Jun. 25, 2013

3.

US 2012/0076830A1

Mar. 29, 2012

A US patent 8,772,032 B2 describes the application of ability of the metallic nanoparticles

like Cerium Oxide to stimulate the proliferation of stem cells in vivo or in vitro. A US patent
8,469,034 B2 describes a novel method for manipulating stem cells ex vivo or in vivo using
magnetic particles and the methods of treatment related the stem cell disorder using magnetic
field gradient.

The US Patent US 2012/0076830A1describes stem cells, and other

progenitors can be stimulated to differentiate into different cell types using nanoparticles and
electromagnetic stimulation. The invention provides a technique for differentiating
mesenchymal stem cells (MSCs) into osteoblasts and other connective tissue.
BACKGROUND OF THE INVENTION
The stem cells based therapies are currently one of the most promising and exciting areas that
will lead to disease treatment and reparative medicine. But the problem in stem cell therapies
is stem cell targeting to the site of interest, differentiating into desired cell type and
monitoring. The stem cell targeting to the injured site or diseased part and held them at those
sites is most important. But to all these problems associated with stem cell therapies can be
unfold using nanoparticles.
U.S. Patent No. 6,548,264 explains the magnetic nanoparticles based application in the field
of diagnostic, imaging and recording systems. These magnetic nanoparticles consist of a
metal magnetic core with silica coating. As the core of magnetic nanoparticles consist of a
magnetic material that helps the nanoparticles to be a response to a magnetic field.
Magnetic nanoparticles are types of nanoparticle whose properties can be manipulated by
applying the magnetic field gradients. These magnetic particles commonly consist of the
magnetic elements core such as nickel, cobalt and iron and their compounds.There have been
many recent developments in synthesis, characterization and applications biocompatible

magnet nanoparticle in the field of health care. In these systems therapeutic application,
magnetic carrier particles are attached to drugs or genes. Th magnetic particles conjugated
with drugs, or genes are localized by the application of spatially focused high gradient
magnetic fields at the target site in vivo. Once the accumulation of the target site by
nanoparticle drug conjugate. Then the release of drug and uptake at the sites is enhanced. A
wide variety of stem cell receptor types can be targeted and activated using nanoparticles and
magnetic particles.
Nanobiomaterials have promising applications in the biomedical and regenerative medicine
in areas including tissue engineering, drug delivery, biosensors, and bioimaging. The
nanoparticles like gold nanoparticles (GNPs) and single-Walled carbon nanotubes (SWNTs)
have potential for diagnostic and therapeutic applications because of their ability to
conjugated with biological molecules, and have useful mechanical, electrical, and physical
properties. SWNTs and GNPs can absorb radio-frequency electromagnetic radiation and light
in the near infrared (NIR) which will lead to a localized increase in temperature. This feature
of the nanoparticles can be used in the tumor treatment such that nanoparticles are localized
in tumor tissue. When these absorb radio-frequency electromagnetic radiation and light in the
near infrared (NIR) will lead to a localized increase in temperature that will cause tumor
destruction due to induced hyperthermia. When the electromagnetic radiation is in a
frequency range, that is poorly absorbed by healthy tissue that will only cause thermal
ablation only occurs by localizing of nanoparticles.
SUMMARY OF THE INVENTION
The magnetic nanoparticles tagged or crosslinked with stem cell can be delivered to or held at
a particular repair site by the application of spatially focused high gradient magnetic fields.
The specific cellular membrane receptors that involve localizing stem cells at a repair site
retaining the cells at the site and remotely activating these stem cells in situ within the patient
can be done using magnetic nanoparticles. The stem cell receptor such as mechano-activated
ion channels e.g. calcium channels, integrins, K+ channels (TREK), and surface membrane
binding sites such as RGD, present in human bone marrow stem cells can be activated.
Importantly, The remote activation of such potential receptors can be done using magnetic
nanoparticles. The targeting of known receptors such as external growth factors like TGFB

and BMP2, which have been known to activate downstream transcription factors such as
Runx2 and Osterix that for critical for stem cell differentiation.
1. Magnetic Particles Based
Magnetic nanoparticles that belong to a class of nanoparticle whose properties changed easily
in the presence of magnetic field gradients. Biocompatible magnetic nanoparticles consist of
a magnetite (Fe3O4) and/or maghemite (Fe2O3) core with coatings of organic materials like
silica, dextran, or PVA.
1.1 Preparation of Stem cell-Magnetic particle Conjugate
Biocompatible magnetic nanoparticles that consist of a magnetite (Fe3O4) and/or maghemite
(Fe2O3) core with a coating of silica, dextran, or PVA coating is used. These particles can
range from l0 nm up to a few microns in size that are functionalized and crosslinked to
membrane attachment motifs. A magnetic nanoparticle with a verity of organic compounds
for binding, delivery and activation of stem cells.
1.2 Targeting of Stem cell-Magnetic particle Conjugate
Conventionally the known external high-gradient magnet is used to target the stem cells to
specific sites within an in vitro or in vivo. Such high field or gradient products which will
exert a translational force on the magnetic particles loaded into the cells, holding them at the
target site.
1.3 Activation of Stem cell or Specific ion channel/cell receptor for differentiation using
Magnetic particle
The principle behind ion channel activation using magnetic particles is that ion channels
change conformational state chance from closed to open or vice versa in response to forces
created by external magnetic force gradient. As such ion channels can be activated using
magnetizable particle provided that by coupling the magnetizable nanoparticles with either
directly or indirectly of the ion channel protein at the mechanoresponsive region. The
activation of ion channels may be done by attaching one or more specific antibodies or
protein binding motifs to the magnetizable particles. Thus, these magnetizable particles
recognize cellular membrane and/ or the ion channels by recognizing specific receptors of

the respective ion channels. Thus, the ion channels can be remotely activated using
mechanical forces created by the magnetic particles under the influence of magnetic field.
The method is especially advantageous since it provides treatment of a huge variety of
disorders where key role played by one or more ion channels associated with these disorders.
This invention provides a potential method for control of disorders by ion channel activation
including pain relief, e. g. an aesthetic role.
This method will provide a novel treatment of a patient suffering from a disorder in which an
ion channel plays a role and magnetizable nanoparticles which comprises the administration
to such a patient of as hereinbefore described and manipulating those particles using a
magnetic field.
2. Metal and Carbon based nanoparticles for Stem cell differentiation
The term metal nanoparticle is used to define nano-sized particles of metals in dimensions
within the range of 1-100nm. Metallic nanoparticles over a century have fascinated scientist
that we find that the metal and metal oxide nanoparticles have found utilization recently in
the field of biomedical sciences and engineering. They have a tremendous focus of interest
because of their huge potential in nanotechnology. As these nanoparticles can be synthesized
and allows the modification of these nanoparticles with various chemical functional groups.
Thus, this allows conjugation of nanoparticles with drugs of interest antibodies and ligands.
These are a vast potential applications of nanoparticles in the field biotechnology, magnetic
separation, drug delivery and gene delivery and more importantly diagnostic imaging, etc.
Carbon nanoparticles including but not limited to carbon nanotubes, single walled carbon
nanotubes (SWNTs), graphene nanoparticles, and graphite nanoparticles.
2.1 Proliferation of stem cells using metallic nanoparticles like Cerium Oxide
The stem cell has the ability differentiate into any cell type of interest. Whereas the
environment required for stem cell proliferate and differentiate most important. Thus,

The

environment may be further modified by the provision of influencing factors like

nanoparticles or the toxic or undesired agents in the environment has been cleaned. The
growth and division rates of stem cell increased the oxidative stress on the stem cells lowered
or decreased. These can be done by administering cerium oxide nanoparticle along with stem

cell to a body. The cerium oxide nanoparticle is injected into the site body that allow these
particles to be contacted with the stem cells. As cerium oxide can lower oxidative stress that
will favor the environment for the stem cells proliferation and differentiation.
2.2 Stem cell differentiation by Nanoparticles using electromagnetic radiation
The stem cells and other progenitor cells can be simulated using nanoparticles that absorb
electromagnetic radiation and transmit mechanical energy to the cells. These nanoparticles
include carbon or gold nanoparticles. A stem cell can be allowed proliferate and differentiate
by culturing the cell in culture media by the presence of nanoparticles, and subjecting the cell
culture to electromagnetic radiation to induce mechanical resonance of the particles. The
properties of the nanoparticles like The electromagnetic and optical absorbance depend on the
size, the composition of the nanoparticles themselves and moieties or functional groups
linked to the nanoparticles. Nanoparticles are subject to electromagnetic radiation at a
frequency and intensity that results in conversion electromagnetic radiation to acoustic
energy. This acoustic energy produced by the nanoparticle is utilized for the stimulation of
stem cells or other progenitor cells.

Conclusion:
Stem cell-based therapies are currently emerging as a promising strategy that will lead to
tackle genetic disorder, cancer, disease treatment, and reparative medicine. But this Stem
cell-based therapies is associated with a potential problem such as targeting, holding,
activating and differentiating the stem cell to the site of interest, differentiating into desired
cell type. The application of nanoparticles in the field of stem cell therapies can unfold all the
associated potential problem with stem cell therapies.
Reference:
1. Kiminohu Sugaya and Sudipta Seal; Methods and materials for stimulating proliferation
of stem cells; Publication number US8772032 B2; Publication date Jul 8, 2014.
2. Jon Dobson and Alicia El Haj; Stem cell targeting and activation using magnetic
particles; Publication number US8469034 B2; Publication date Jun 25, 2013.
3. Balaji Sitharaman and Longtin Jon; Differentiation of stem cells with nanoparticles,
Publication number US 2012/0076830A1; Publication date Mar 29, 2012.