NANOSTRUCTURED MATERIALS FOR

BIOMEDICAL APPLICATION

Submitted by:
B.PARAMESHWARI,
I st BIO-TECH,
PERIYAR MANIAMMAI UNIVERSITY,
VALLAM, THANJAVUR 613 403.
TAMIL NADU.
e-mail: chakambariboopathi@yahoo.com
ABSTRACT:
Adaptation of nano structured materials into biomedical devices and system has been
of great interest in recent years. These modified nano structured materials can bring new
and unique capabilities to a variety of biomedical applications ranging from implant
engineering and modulated drug delivery, to clinical biosensor and diagnostics. This
review describes recent advances of nano structured materials for biomedical applications
the methods used to modify nano structured materials are summarized briefly, while
several current interest in biomedical applications for modified and functionalized nano
structured materials are emphasized.

INTRODUCTION:
Development of nanotechnology in material science and engineering has taken
place in the last decade. Nanostructured materials refer to certain materials with delicate
structures of small size, falling in the 1- 100 nm range, and specify properties and
functions related to the size effect. This does not come as a surprise considering that
nanostructured materials have the capability to be adapted and integrated into Bio-
Medical devices, since most biological systems including viruses, membrane and protein
complex, exhibit natural nanostructures. Currently medicine and Biomedical engineering
among the most promising and challenging fields involved in the applications of
nanostructured materials. Rapid advancement of nanostructured material have been made
in a wide variety of Biomedical applications,

THE BIOMEDICAL APPLICATIONS FOR THE MODIFICATIONS OF

NANOSTRUCTURED MATERIALS
TISSUE AND IMPLANT ENGINEERING :
As emerging area, tissue and implant engineering are evolving to address the
shortage of human tissue and organs. The core of the tissue engineering and regenerative
medicines are the fabrications of scaffolds, in which a given cell population is seeded,
proliferated and differentiated with the introduction of functional cell types from many
different sources. Nanostructured materials and their modified forms of sum attractive
possibilities in the fields of tissue and implant engineering. Bone-like nanostructured
scaffolds have been developed using the technology of composites to imitate natural bone
in bone tissue engineering. Magnetic nanoparticles have been used in cell isolation and
purification for tissue engineering and other application. Nanoparticles can be conjucted
with intency, stable fluorescence for tracing cells through several generations, which is
ideal for the study migration motility morphology and other cell function.
BONE IMPLANT:
Currently, implants and scaffolds for bone repair and regeneration are of
considerable interest for biomedical applications of Nanostructured materials, as natural
bone exhibits certain hierarchical structures of nanometer dimensions within bone
matrices. Infact, compare to respective micro sized counterparts most nanoscale bone
implant materials, such as ceramics(alumina, titania, and hydroxyapatite(HA)),
polymers(PLGA and polyurethane) and metals(Ti,Ti6A14V,and CoCrMo alloy) have
been shown to enhance bone cell responses and functions that include cellular adhesion,
proliferation, synthesis of alkaline phosphatase, and calcium deposition. In spite of the
enhancement of cellular responses, poor mechanical properties of the nanosized implant
materials limit their further applications for bone repair. Poor mechanical properties
restricts clinical use of nano-HA as load-bearing implants, and limits their applications to
small, unloaded and lightly-loaded implants, powders, coatings, composites, and porous
scaffolds for tissue engineering furthermore, the bending modulus of nanophase alumina
was 1.8times greater than that of natural human femur, bone, even though the nanophase
ceramics has closer bending properties to native bone than conventional ceramic.
Mismatch in elastic modulus between alumina and the surrounding bone often causes
stress shield effect in bone tissue, resulting in bone resorption and loosening of implants.
To compensate for this weak feature, modifications of nanostructured bone implant
material are needed to improve their mechanical properties. Appropriate modification can
also further reinforce the interface between bone cells and the implant matrix. Different
methods have been proposed to modify existing nanostructured materials for bone
implants.

MODULATED DRUG DELIVERY SYSTEM:

In recent years nanoparticles systems, including solid nano particles,
polymeric nano particles, and polymeric self assemblies, have attracted increasing
attention for users potential drug delivery systems. The advantage of using nanoparticles
systems for drug delivery result from their two basic properties. First nano particulates,
due to their small size, can penetrate small capillaries and be taken up by cells, which
allows for efficient dug accumulation at target sites in the body. Second, the use of bio
degradable materials for nano particulates preparation allows for sustained drug release
within the target over a period of days or even weeks after administration. Furthermore,
new functions arising from nano-sizing, such as improved solubility, target ability and
adhesion to tissues can be conferred to nano-delivery systems and also provided the
possibilities to covert poorly soluble, poorly absorbable, and predisposed biologically
active substance into promising drugs. In spite of these advantages, however some
technical problem limit clinical applications of these new nanoparticles drug delivery
systems. Some of these limitations include relatively short blood circulation time, low
accessibility to physiologically barriers of target sites (blood brain barrier, lymphatic
barrier, etc) and low efficiency of gene transfect ion. Suitable and effective modification
of these nano particles materials are needed to overcome this technique obstacles.

TARGETTING DELIVERY:
In addition to having enhanced circulation properties, most drug delivery
systems need to target specify cells and tissueses in the body. This leads to increases in
the therapeutic efficiency as well as a decrease of systemic side effects for the
development of novel therapeutic approaches.

BRAIN TARGETTING AND BLOOD BRAIN BARRIER (BBB)

 The BBB, which is formed by the tight endothelial cell junctions of capillaries
within the brain, limits the ability of many drugs to penetrate brain tissues and enter the
central nerves system. The presence of the type junctions and lack of aqueous pathways
between cells greatly restrict the movement of polar solutes across the cerebral
endothelium. In fact, only nonionized, lipophilic and low molecular weight compounds
can cross the BBB by diffusion mechanism. Consequently, the therapeutic value of many
promising drugs is diminished significantly compromising pharmacological treatment for
neurological and psychiatric disorders. Such limitations justify the development of new
strategies for the drug delivery into the CNS. One of the possibilities y\to delivery drug to
the brain is the employment of nanoparticles.
Poly (butyl cyanoacrylate)(PBCA) nanoparticles were the first nanoparticles that
were used for in-vivo drug delivery to the brain. To increases efficacy of nanoparticles
across the BBB, different surface modification methods for nano particles have been
used. Among these, an overcoating nanoparticle with polysorbate 80 has been the most
widely investigated. By using polysorbate 80 overcoated PBCA nanoparticles,
hexapeptide dalargrin, the first drug to cross the BBB via nanoparticles, was successfully
delivered to the brain. After intravenous injection of such nano particles loaded with
dalargin, antinociceptive activity was demonstrated. On the contrary, uncoated dalargin
nanoparticles exhibited no antinociceptive effect. Over coating with polysorbate 20, 40,
60 led to antinociceptive effect similar to those of poysorbate 80, where as other
surfactants such as polyxamers 184, 188, 338, 407, poloxamine 908 had no such effect.
Besides the hexapeptide dalargrin, other antinociceptive agents. Such as the dipeptide
kytorphin and loperamide where tested. Effects similar to those of dalargrin where
abserved. Furthermore, polysorbate 80 coated PBCA nanoparticles where used to deliver
Doxorubicin, an important anti cancer drug, to the brain. The brain concentration of
systematically administrated doxorubicin can be enhanced more than 60- folds over free
doxorubicin deliver by bending to overcoated nanoparticles.
Surface modifications of nanoparticles with PEG another method to enhance drug
delivery to the brain. Calvoetal synthesized PEGylated polycyanoacrylate nano particles
and demonstrated the concentration of PEGylated nanoparticles in the brain and
spinalcord where greatly increased in comparision to conventional non-PEGylated nano
particles. The adsorption of PEG onto hexadecylcyanoacrylate spheres helped to
increases the accumulation of nanospheres in rat normal brain 4-to 8-fold over non-PEG-
coated nanospheres. More recently, PEG contain nanogels where synthesized for the
delivery oligonucleotides potential diagnostic and therapeutic agents for brain cancer and
neurodegenerative disorders in mouse models as a result of incorporation into nanogels 1
h after intravenous injection the accumulation of a phosphorothioate ODN in the brain
was observed to increases by over 15 fold compared to the free ODN.
Presently, the most likely mechanism for drug transport enhancement mediated
by nanoparticles into the brain involves the endocytosis of nano particles by endothelial
cells followed by the release of the drug within the cells to the brain. Research has shown
endocytosis polysorbate 80-coated PBCA nanoparticles by brain blood vessels
endothelial cells in vivo and in vitro. In polysobate overcoated nanoparticles, polysorbate
act as an anchor for apolipoprotein E, which is involved in the transport of LDL into
brain. In PEG modified nano particles, diffusion/convention was main proposed
mechanism for extravasation of nano particles across the altered BBB. PEG-coated nano
particles also displayed an affinity with the brain endothelial cell.

CELL TARGETTING AND TUMOUR DELIVERY OF DRUG:

Delivery therapeutic drugs to specify cells, a specially tumor cells, can lead
siginificant in drug toxicity and increased therapeutic effects on cancer and other
diseases. Antibodies, hormones, or other bio specific ligands have been conjucted with
nanoparticles for this purpose. This modified nano particles can bind and deliver loaded
drugs to specify cells. Low molecular weight targeting agents, such as folic acid, have
been shown to preferentially target cancer cells, due to the frequent over-expressions of
the folate receptor on the surface of the cancer cell. Folic acid bind to the folate receptor
at cell surfaces and is internalized by receptor-mediated endocytosis. Zhang and co-
workers recently modified the surface of super paramagnetic magnetite nano particles
with bio specific ligand of folic acid and then cultured modified the magnetic nano
particles with human breast cancer cells. Their results demonstrated that the
immobilization of folic acid increases the amount of nano particles uptake breast cancer
cells in comparision to unmodified nano particles. Additionally, using the hyperthermia
of magnetic materials when exposed to certain magnetic fields, tumor specify drug
delivery of magnetic nano particles is providing a new method treat cancer called
hyperthermia treatment. By controlling the frequency and strength of alternating
magnetic field, heat is generated in magnetic nanoparticles conducted into the
immediately surrounding diseased tissue. When the temperature is maintained above the
therapeutic threshold of 42 degree centigrade for 30 min or more, the cancer is destroyed.
Folic acid based nano particles have also been successfully used in a novel cancer therapy
(NCT). NCT utilized a stable (non-radio active) nuclide delivered to tumor cells upon
which irradiation by thermal or epithermal neutrons produces localized cytotoxic
radiation. Mumper and co-worker reported that folate ligands can efficiently be coated on
gadolinium nano particles. They also demonstrated that cell uptake and tumor retention of
folate-coated nano particles was significant enhanced over other molecule coated nano
particles, such as PEG coated nano particles.
Hepatocyte- specify targeting materials can perform liver-specify drug delivery
of nano particles. A galactose-carrying polymer is one example of such materials, as the
galactose ligand can be recognized by the asialoglycoprotein receptor of hepatocytes
chos group used poly (vinyl benzyl lactonamide)as a galactose-carrying polymer to coat
PLA nano particles and develop a novel biodegradable nano particles carrier for liver-
specify drug delivery. Their results demonstrated that the increase of internalization of the
modified nano particles by the hepatocytes with time was significantly nano particles
higher than that of the unmodified controls. Internalization process was suggested to be
through a receptor- mediated mechanism.

CLINICAL-BASED BIOSENSOR AND DIAGNOSTICS:Other important biomedical

applications for modified nano structured materials clinical-based bio sensor and
diagnostics. Although still in the developmental stages, nano-sized materials and their
modified derivatives have had a significant impact on clinical based bio analysers. Nano
structured materials of various shapes, sizes, and composition could fundamentally
change the bio analytical measurement landscape. by by the transducer, which converts
the information into electrical or optical signals. based on different clinical analytes and
purposes, clinical bio-sensor can be categorized as antibody or antigen(Protein) bio-
sensor, DNA-biosensor, metabolic(glucose) monitoring bio-sensor, intra cellular bio-
sensor etc.

DNA BIOSENSORS:
Biosensor for DNA or based on the process of hybridization, the matching of
strand DNA with its complementary. These biosensors can be used for recognition and
quantization of target DNA is clinical samples. DNA analysers is widely considered to be
the most recent and promising use of biosensor for clinical applications, especially for
genomeric sequencing, mutation detection, and pathogen identification of inherited
disease. Similar to antibody and antigen biosensor, the introduction of nanostructured
materials with appropriate modification into DNA biosensor greatly improves properties
including sensitivity broadening of analysers.
Bimolecular grafting, or coupling, is one of the main ways to modify nano-
structured materials for DNA biosensors. DNA-functionalized gold nano particles have
been used quartz crystal microbalance (QCM) to enhance DNA sensor sensitivity. In
order to avoid the high negative charge density of DNA , neutral peptide nucleic
acid(PNA),DNA analogues with the entire sugar-phosphate backbone replaced by a
polyamide backbone, have been prepared to modify gold nano crystals for DNA sensing.
The PNA complexes could offer nano materials with two distinct advantages: 1) greater
stability than DNA duplexes and 2) greater mismatch sensitivity. The latter feature
enables PNA- modified nanoparticles to act as highly selective nanoscale sensors. Further
more when coupled with a substantial change in colloidal stability upon DNA
hybridization, PNA- modified nanoparticles can be used to developed novel colorimetric
DNA assays that detect the presence of single pase imperfections within minutes. In
addition, Xiaetal. Investigated streptavidin conjugated cadmium selenide semiconductor
nanocryspals as fluorescent probes for human mepaphases chromosomes. They
demonstrated that the fluorescence of the modified nanocrystal fluorophores was
significantly brighter and more photostable then organ fluorothore texas red and
fluoresein.

CONCLUSIONS:
The biocompatibility and bio functionality of nano particles to be further
improved and long term clinical evalutions of modified nanoparticles in vivo needed to
be performed. Precise and multi-site modification of nano particles, especially
Asymmetric nano particles, have not yet been investigated. Also, inefficiencies of nano
particles modified with macro molecules, due to steric hindrances, need to be
overcome.with the development of nanotechnologies, medicine, and biomedical
engineering, all of these problems have the potential to be solved, and more nano
structured materials with more biological properties and function to be developed and
used in the wide variety of clinical practices and bio medical devices and system.