INTRODUCTION to various disorders or injuries, such as

INTRODUCTION

 

Bone possesses the
intrinsic capacity for regeneration as part of the repair process in response
to injury, as well as during skeletal development or continuous remodelling throughout
adult life 1,2. Bone regeneration is comprised of a
well-orchestrated series of biological events of bone induction and conduction,
involving a number of cell types and intracellular and extracellular molecular signalling
pathways, with a definable temporal and spatial sequence, in an effort to optimise
skeletal repair and restore skeletal function 2,3.

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Regenerative medicine
attempts to restore living tissue which has been lost or damaged. It is a
highly interdisciplinary field which has only been made possible by the
intersection of recent advances in stem cell therapy, bioengineering, and
nanotechnology.

The rapid
expansion of nanotechnology during the past ten years has led to new
perspectives and advances in biomedical research as well as in clinical practice.
As nanotechnology is defined by the size of a material (generally 1–100 nm) or
manipulation on the molecular level, it involves a broad range of nanoscaled materials
used in various fields of regenerative medicine, including tissue engineering
(TE), cell therapy, diagnosis and drug and gene delivery.

The basic strategy
of TE is the construction of a biocompatible scaffold that, in combination with
living cells and/or bioactive molecules, replaces, regenerates or repairs
damaged cells or tissue. The crucial scaffold requirements include
biocompatibility, controlled porosity and permeability, suitable physical
properties comparable to the targeted tissue and, additionally, support for
cell attachment and proliferation. To promote cell adhesion and growth, the
addition of nanotopographies to the biomaterial surface improves its
bioadhesive properties, e.g. the surface roughness, aside from the chemistry,
is an important factor influencing cell attachment and spreading.The large
surface area of nanostructured materials enhances the adsorption of adhesive
proteins such as fibronectin and vitronectin, which mediate cell-surface
interactions through integrin cell surface receptors (1,2).

The use of cell therapy
in regenerative medicine has been extensively examined to replace cells lost
due to various disorders or injuries, such as Parkinson’s disease, ischemic
stroke, diabetes, myocardial infarction, etc. Further progress in cell therapy
leading to clinical trials requires the crucial use of non-invasive techniques
for monitoring the efficacy of cell therapy and graft survival in the host
organism. To allow cell detection in vivo, superparamagnetic iron oxide
nanoparticles (SPIO) have been successfully used to label transplanted
cells for in vivo monitoring by highresolution magnetic resonance imaging
(MRI). MRI cell tracking has been used for monitoring various cells and organs,
such as the brain and spinal cord, pancreas, heart, liver and kidney. To cover
some of the recent trends in regenerative medicine, this review will focus on
the use of nanotechnology in TE and cell therapy for Bone Tissues. New
approaches to the application of nanofibers for bone tissue regeneration will be
outlined and discussed. Recent trends towards utilizing SPIO nanoparticles for
cell tracking, with a particular focus on cell monitoring in the central nervous
system, will be further examined. With regard to the broadness of this topic,
other interesting and contemporary issues of nanotechnology in regenerative medicine,
such as carbon nanotubes and nanofibers, nano-enabled drug delivery (3) and
surface nanotopography (4), are not included in this review as they have been
described in detail elsewhere.

Bone
regeneration

The bone tissue is a mineralised organic
matrix mostly formed from collagenous fibers and calcium phosphate in the form
of hydroxyapatite (HA), with embedded osteoblasts, osteocytes and osteoclasts
as cell components. To design scaffolds for bone reconstruction, suitable
biophysical properties, such as hardness and porosity, as well as support for
cell growth and differentiation, must be provided. In the past several years,
various nanofibrous matrices produced by a variety of techniques have been
explored for bone reconstruction. The growth of osteoblastic cells and the
osteogenic differentiation of bone marrow-derived MSCs was demonstrated on natural
collagen or silk fibroin polymers, PLA, PCL and PLGA degradable synthetic
polymers as well as on blends of synthetic polymers and natural polymers such
as gelatin, collagen, silk fibroin and chitosan; all of these materials have
been summarized by Jang et al. (44). To improve the mechanical properties of
biodegradable polymers, composite electrospun nanofibers with incorporated HA
have been prepared using several methods. The effect of HA mineralisation of nanofibrous
substrates on osteoblast responses has been demonstrated on HA composites with
PLLA, PLGA, gelatin, collagen and chitosan as well as on other HA composite
nanofibers (44). A combination of bone morphogenic protein 2 (BMP-2) and HA nanoparticles
encapsulated into silk electrospun matrices has been shown to synergistically
enhance bone formation from seeded human MSCs (45). SAPN that filled the pores
of a titanium foam were used to transform the inert titanium foam into a potentially
bioactive bone implant. This hybrid bone implant allowed the encapsulation of
osteoblasts, and the implantation of this SAPN/porous titanium scaffold into
rat femurs led to new bone formation around and inside the implant, which could
be used to improve the mineralization, fixation, osteointegration and stability
of orthopedic or dental implants (46). In another report, peptide-amphiphile self-assembled
nanostructures containing a peptide sequence from osteogenic peptide BMP-2 have
been developed as a three-dimensional scaffolding material that promotes the
osteoblastic differentiation of human bone marrow MSCs (47).

Previous studies demonstrated greater
bone-forming cell (osteoblast) functions on various nano-materials, such as nano-hydroxyapatite
(Sato et al. 2005), electro-spun silk (Jin et al. 2004), anodized titanium (Yao
et al. 2008) and nano-structured titanium surfaces as compared to conventional orthopedic
implant materials (Khang et al. 2008; Webster et al. 1999). As a next step,
efforts have focused on understanding the mechanisms of enhanced bone cell functions
on these materials and these studies have provided clear evidence that altered
amounts and bioactivity of adsorbed proteins (such as vitronectin, fibronectin and
collagen) were responsible due to increased surface energy of nanostructured
surfaces (Khang et al. 2007; Webster et al. 2001). In addition to these
observed greater initial responses of osteoblasts, longer term functions of
bone cells (such as calcium and phosphate mineral deposition (CaP)) crucial for
osseointegration of orthopaedic implants are promoted on nanostructured
biomaterials (Ergun et al. 2008; Webster 2003). In this manner, nanophase titanium,
Ti6AlV4, and CoCrMo have all promoted greater calcium crystallization (CaP)
compared to microphase samples of these same materials (Ward and Webster 2006).
Recent studies have also shown that bone cells respond differently on submicron
and nanometer scale titanium surfaces, despite the minimal size difference between
these two surface topographies (Khang et al. 2008). In fact, it has been demonstrated
that small changes in nanometer surface features can have larger consequences towards
bone regeneration (Khang et al. 2008). Another design parameter, using aligned
nanometer surface features on metals, has also proven to further mimic the
natural anisotropy of natural bone to promote bone cell functions (Khang et al.
2008). Each of these studies provided clear evidence that bone cell behavior is
strongly dependent upon the size of surface features where nanometer and
submicron sized surface features (Fig. 4) can substantially improve long term functions
of bone cells. For these reasons, in the near future, it is strongly believed
that these optimized nanotextured implant materials will enter
commercialization in the orthopedic as well as dental markets; some
nanomaterials have already received FDA approval for human implantation (Sato
and Webster 2004).