INTRODUCTION Bone possesses theintrinsic capacity for regeneration as part of the repair process in responseto injury, as well as during skeletal development or continuous remodelling throughoutadult life 1,2. Bone regeneration is comprised of awell-orchestrated series of biological events of bone induction and conduction,involving a number of cell types and intracellular and extracellular molecular signallingpathways, with a definable temporal and spatial sequence, in an effort to optimiseskeletal repair and restore skeletal function 2,3.Regenerative medicineattempts to restore living tissue which has been lost or damaged. It is ahighly interdisciplinary field which has only been made possible by theintersection of recent advances in stem cell therapy, bioengineering, andnanotechnology.

The rapidexpansion of nanotechnology during the past ten years has led to newperspectives 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) ormanipulation on the molecular level, it involves a broad range of nanoscaled materialsused in various fields of regenerative medicine, including tissue engineering(TE), cell therapy, diagnosis and drug and gene delivery.The basic strategyof TE is the construction of a biocompatible scaffold that, in combination withliving cells and/or bioactive molecules, replaces, regenerates or repairsdamaged cells or tissue. The crucial scaffold requirements includebiocompatibility, controlled porosity and permeability, suitable physicalproperties comparable to the targeted tissue and, additionally, support forcell attachment and proliferation. To promote cell adhesion and growth, theaddition of nanotopographies to the biomaterial surface improves itsbioadhesive properties, e.g.

the surface roughness, aside from the chemistry,is an important factor influencing cell attachment and spreading.The largesurface area of nanostructured materials enhances the adsorption of adhesiveproteins such as fibronectin and vitronectin, which mediate cell-surfaceinteractions through integrin cell surface receptors (1,2).The use of cell therapyin regenerative medicine has been extensively examined to replace cells lostdue to various disorders or injuries, such as Parkinson’s disease, ischemicstroke, diabetes, myocardial infarction, etc.

Further progress in cell therapyleading to clinical trials requires the crucial use of non-invasive techniquesfor monitoring the efficacy of cell therapy and graft survival in the hostorganism. To allow cell detection in vivo, superparamagnetic iron oxidenanoparticles (SPIO) have been successfully used to label transplantedcells 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 coversome of the recent trends in regenerative medicine, this review will focus onthe use of nanotechnology in TE and cell therapy for Bone Tissues.

Newapproaches to the application of nanofibers for bone tissue regeneration will beoutlined and discussed. Recent trends towards utilizing SPIO nanoparticles forcell tracking, with a particular focus on cell monitoring in the central nervoussystem, 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) andsurface nanotopography (4), are not included in this review as they have beendescribed in detail elsewhere.BoneregenerationThe bone tissue is a mineralised organicmatrix mostly formed from collagenous fibers and calcium phosphate in the formof hydroxyapatite (HA), with embedded osteoblasts, osteocytes and osteoclastsas cell components. To design scaffolds for bone reconstruction, suitablebiophysical properties, such as hardness and porosity, as well as support forcell growth and differentiation, must be provided.

In the past several years,various nanofibrous matrices produced by a variety of techniques have beenexplored for bone reconstruction. The growth of osteoblastic cells and theosteogenic differentiation of bone marrow-derived MSCs was demonstrated on naturalcollagen or silk fibroin polymers, PLA, PCL and PLGA degradable syntheticpolymers as well as on blends of synthetic polymers and natural polymers suchas gelatin, collagen, silk fibroin and chitosan; all of these materials havebeen summarized by Jang et al. (44). To improve the mechanical properties ofbiodegradable polymers, composite electrospun nanofibers with incorporated HAhave been prepared using several methods. The effect of HA mineralisation of nanofibroussubstrates on osteoblast responses has been demonstrated on HA composites withPLLA, PLGA, gelatin, collagen and chitosan as well as on other HA compositenanofibers (44).

A combination of bone morphogenic protein 2 (BMP-2) and HA nanoparticlesencapsulated into silk electrospun matrices has been shown to synergisticallyenhance bone formation from seeded human MSCs (45). SAPN that filled the poresof a titanium foam were used to transform the inert titanium foam into a potentiallybioactive bone implant. This hybrid bone implant allowed the encapsulation ofosteoblasts, and the implantation of this SAPN/porous titanium scaffold intorat femurs led to new bone formation around and inside the implant, which couldbe used to improve the mineralization, fixation, osteointegration and stabilityof orthopedic or dental implants (46). In another report, peptide-amphiphile self-assemblednanostructures containing a peptide sequence from osteogenic peptide BMP-2 havebeen developed as a three-dimensional scaffolding material that promotes theosteoblastic differentiation of human bone marrow MSCs (47).Previous studies demonstrated greaterbone-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 (Yaoet al. 2008) and nano-structured titanium surfaces as compared to conventional orthopedicimplant materials (Khang et al.

2008; Webster et al. 1999). As a next step,efforts have focused on understanding the mechanisms of enhanced bone cell functionson these materials and these studies have provided clear evidence that alteredamounts and bioactivity of adsorbed proteins (such as vitronectin, fibronectin andcollagen) were responsible due to increased surface energy of nanostructuredsurfaces (Khang et al. 2007; Webster et al. 2001). In addition to theseobserved greater initial responses of osteoblasts, longer term functions ofbone cells (such as calcium and phosphate mineral deposition (CaP)) crucial forosseointegration of orthopaedic implants are promoted on nanostructuredbiomaterials (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 submicronand nanometer scale titanium surfaces, despite the minimal size difference betweenthese two surface topographies (Khang et al. 2008). In fact, it has been demonstratedthat small changes in nanometer surface features can have larger consequences towardsbone regeneration (Khang et al. 2008).

Another design parameter, using alignednanometer surface features on metals, has also proven to further mimic thenatural anisotropy of natural bone to promote bone cell functions (Khang et al.2008). Each of these studies provided clear evidence that bone cell behavior isstrongly dependent upon the size of surface features where nanometer andsubmicron sized surface features (Fig. 4) can substantially improve long term functionsof bone cells. For these reasons, in the near future, it is strongly believedthat these optimized nanotextured implant materials will entercommercialization in the orthopedic as well as dental markets; somenanomaterials have already received FDA approval for human implantation (Satoand Webster 2004).

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