Nanotechnology and its role inthe management of periodontaldiseases

LING XUE KONG, ZHENG PENG, SI-DONG LI & P. MARK BARTOLD

With the unstoppable trend of an increasing aging

population in both the developing and developed

countries, scientists in the field of regenerative

medicine and tissue engineering are continually

looking for new ways to apply the principles of cell

transplantation, materials science, and bioengineer-

ing to construct biological substitutes that will restore

and maintain normal function in diseased and

injured tissues (2). In addition, the development of

more refined means of delivering medications at

therapeutic levels to specific sites is an important

clinical issue. Applications of such technology in

dentistry, and periodontics in particular, are no

exception as periodontal destruction can be found to

increase in prevalence with increasing age (42, 52).

The traditional clinical procedures of scaling, root

planning and periodontal flap surgery, if followed by

an adequate postoperative supportive periodontal

care, results, in most cases, in successful manage-

ment of progressive periodontal diseases (27, 62, 65).

More recently, the regenerative treatment of perio-

dontal defects with an agent, or procedure, has

attracted enormous interest from materials scientists

and also from both private companies and govern-

ment organizations because of its considerable eco-

nomic potential (4, 43) and scientific significance.

One of the emerging areas is tissue engineering that

seeks to develop techniques andmaterials to aid in the

formation of new tissues to replace damaged tissues

(4). Guided tissue engineering has been successfully

used in the treatment intrabony defects (14) and fur-

cation defects (45, 65). A more general review of tissue

engineering concepts in terms of periodontal regen-

eration has been carried out by Bartold et al. (4).

The necessary strategies for complete regeneration

of human tissues should be the ultimate endpoint for

the field of regenerative medicine and engineering.

However, for many tissues this goal remains elusive

(74). Nonetheless, there has been significant progress

made in recent years with the development and

introduction of various metallic and polymeric

materials structured in nanoscales (17, 46, 75, 84) and

the development of many biomaterials that form

ideal interfaces with tissues (7, 84). Using natural

processes as a guide, substantial advances have been

made at the interface of nanomaterials and biology,

including the fabrication of nanofiber materials for

three-dimensional cell culture and tissue engineering

(84). One example of such applications in the man-

agement of periodontal diseases is the evaluation of

two typical cellular components of a hard ⁄ soft tissueinterface such as the periodontal ligament ⁄ mandible

and patellar tendon ⁄ tibia (7). Tissue engineering of

such complex interfaces requires a contiguous scaf-

fold system with at least two cell types associated

with the engineering of both hard and soft connective

tissues.

In the pharmaceutical domain, liposomes and

polymer-based micro- and nanoparticles are the

subject of current intense research and development

(72). In addition, metallic particles, which were first

introduced in the first half of the 1980s, are now

experiencing a renaissance. A very new generation of

biosensors based on the optical properties of col-

loidal gold nanocrystals and nanoparticles is ready

to be implemented in diagnosis and medical ima-

ging (72) as well as tagging DNA sandwich assays

(19, 57). Concerning therapeutic applications, the

potential of metallic and polymeric nanoparticles to

help fulfill the need for timely and accurate con-

trolled release of drugs can be explored by syn-

thesizing materials of tailor-designed structures,

such as hybrid hollow spheres (9) and core-shell

structures (11).

184

Periodontology 2000, Vol. 40, 2006, 184–196

Printed in the UK. All rights reserved

Copyright � Blackwell Munksgaard 2006

PERIODONTOLOGY 2000

From the definition provided by the National

Nanotechnology Initiative, nanotechnology exploits

specific phenomena and direct manipulation of

materials on the nanoscale (28). However, nano-

technology is much more than the study of small

things; it is the research and development of mate-

rials, devices, and systems exhibiting physical,

chemical, and biological properties that are different

from those found on a larger scale. Thus nanotech-

nology can be best understood as a broad collection

of technologies – from diverse fields such as physics,

materials science, engineering, chemistry, biochem-

istry, medicine, and optics – each of which may have

different characteristics and applications. Therefore,

it is not the intention of this review to cover the

development of nanotechnology in all areas and its

impact on periodontal diseases. Rather, it will focus

on the development of nanomaterials and their

potential to be used in managing periodontal dis-

eases, including diagnosis and treatment.

Nanomaterials and self-assembly

Nanomaterials are those materials with components

less than 100 nm in at least one dimension, including

clusters of atoms, grains less than 100 nm in size,

fibers that are less than 100 nm diameter, films less

than 100 nm in thickness, nanoholes, and compos-

ites that are a combination of these. The composition

can be any combination of naturally occurring ele-

ments.

Because nanoparticles have significant surface

effects, size effects, and quantum effects,

nanocomposites usually exhibit much better per-

formance properties than traditional materials. The

improved relevant properties include enhanced

toughness, stiffness, improved transparency, in-

creased scratch, abrasion, solvent and heat resist-

ance, and decreased gas permeability. In addition,

nanoparticles have special properties, including

chemical, optical, magnetic, and electro-optical

properties, which differ from those of either indi-

vidual molecules or bulk species. These significant

properties of nanoparticles meet the intriguing

demand to design multifunctional nanocomposite

films, which cover properties of both inorganic and

organic materials and exhibit immense prospects

for developing light-emitting diodes, nonlinear op-

tical devices, resistors, sensors, electrically conduc-

tive films, and gas separation membranes.

Inorganic nanoparticles either currently in use or

under development include semiconductor

nanoparticles (24), metal nanoparticles (22), metal

oxide nanoparticles (10), silica nanoparticles (21),

polyoxometalates (30) and gold nanocrystals (19).

Another important feature of nanostructured

materials is the development of self-assembly. Here,

an autonomous organization of components into

patterns or structures without human intervention

occurs (80). The whole process can be manipulated

and facilitated through the correct setting of condi-

tions (3, 58). Importantly, in the context of self-

assembly of nanostructures there is the simple

concept that cells and tissues self-assemble, and thus

understanding life will require an understanding of

self-assembly. Cells and tissues also offer countless

examples of functional self-assembly that stimulate

the design of nonliving systems. Indeed, self-assem-

bly is one of the few practical strategies for making

ensembles of nanostructures and is therefore the

essential part of nanotechnology. Self-assembly is

common to many dynamics, multicomponents sys-

tems, from smart materials and self-healing struc-

tures to netted sensors and computer networks.

Self-assembly has been classified into static and

dynamic processes based on whether the system

dissipates energy (80). In static self-assembly, for-

mation of ordered structure requires energy but it is

stable once it is formed.

When choosing a material for self-assembly, the

materials should have a critical number of charged

groups, below which the assembling procedure does

not work at all. To form a well-defined stable multi-

layer, the appropriate opposite charge density is

required for the matched materials. To facilitate

analytical studies, the materials should bear some

functional groups, which can be detected by analyt-

ical instruments.

Polyelectrolyte materials bearing a number of

charged groups are most commonly used in self-

assembly as they enable stable, smooth, homogeneous

films to be formedwith anumber of functional groups.

The most widely used polyelectrolytes to date are

commercially available polymers. The cationic poly-

electrolytes include poly(ethyleneimine), poly(all-

ylamine), poly(diallyldimethylammonium chloride),

poly(allylamine hydrochloride), and diazo-resin. The

anionic polyelectrolytes are poly(styrene sulfonate),

poly(vinylsulfate) and poly(acrylic acid). Of these, the

best studied systems are poly(allylamine) ⁄ poly(sty-rene sulfonate) and diazo resin ⁄ poly(styrene sulfo-

nate) (6). Other polymers of current interest include

polyaniline, poly(vinyl pyrrolidone), poly(vinyl alco-

hol) (55, 56), poly(acrylamide), and poly(ethylene

oxide) (73).

185

Nanotechnology and periodontics

The most universal driving forces for establishing

self-assembly are electrostatic attractive interactions

between positive and negative charges. Other inter-

actions such as hydrophobic interactions (37, 81),

charge transfer interactions (69), H-bonding, coordi-

nation bonding (32) and covalent bonding are also

emerging as important forces to be harnessed for

self-assembly purposes.

Self assembly of extracellularmatrices

The regeneration of hard and soft tissues around a

solid implant, or development of new tissues to

replace implanted biodegradable materials, will pro-

vide new vistas in the field of tissue regeneration. At

present, one of the major challenges in this field is to

integrate different functions into synthetic extracel-

lular matrices. Such matrices will ideally behave as a

mechanically sound adhesive, allowing immediate

fixation of the implant before cell-mediated proces-

ses take over the tissue regeneration processes (4, 74).

Most importantly, the synthetic extracellular matrix

will need to perform functions such as to sustain cell

viability and proliferation, allow the establishment of

a blood vessel network formation and provide suffi-

cient support to prevent tissue collapse (74).

It has been demonstrated that well organized self-

assembled nanostructures can be fabricated (44, 54,

76, 80). Within this class of structures are three dif-

ferent classes of block copolymer type architectures –

coil–coil diblock copolymers, rod–coil diblock co-

polymers, and rod–coil diblock oligomers (35). An

example of such a nanostructure is shown in Fig. 1

(76) in which the synthetic structure, analogous to

folded proteins in the definition of chemical sectors,

shape and topography, builds blocks for materials

that pack in ways that fill the space efficiently. It is

noticed (76) that flat objects such as two-dimensional

polymers are likely to form layered structures,

tubules and rods align uniaxially, and identically

shaped and sized nanostructures such as the paral-

lelepipeds are likely to tile into a wide variety of

superlattices (Fig. 1). Three-dimensional packing can

also been easily predicted and fabricated if simple

geometrical shapes such as flat objects, rods, and

tubules are used.

In recent times, developments in this field have

seen the use of pH-induced self-assembly of a pep-

tide-amphiphile to artificially construct a nano-

structured fibrous scaffold with the structural

features of extracellular matrix. Furthermore, after

cross-linking, the newly produced fibers are able to

direct mineralization of hydroxyapatite to form a

composite material in which the crystallographic

axes of hydroxyapatite are aligned with the long axes

of the fibers. This alignment appears to be the same

as that observed in vivo between collagen fibrils and

hydroxyapatite crystals in bone (25). Other develop-

ments have included the synthesis and characteri-

zation of a series of self-assembling biomaterials with

molecular features designed to interact with cells and

scaffolds for tissue regeneration (29).

Nanomaterials with sphericalnanoparticles

The prospect of a new generation of materials based

on the assembly of nanoparticles into spatially

extended two- and three-dimensional arrangements

is a major driving force in the rapidly emerging field

of nanomaterial research (20). Nanoparticles, the

�designer molecules� which govern the macroscopic

behavior of these novel materials, can be constructed

according to a vast range of design principles,

promising unprecedented tuning of material prop-

erties (33). Uniformly distributing inorganic nano-

particles into polymer matrices without aggregation

is one of the most important criteria in preparing

polymeric ⁄ inorganic nanocomposites (PINs).

Decher (16) introduced a method that allows the

construction of multilayer assemblies based on layer-

by-layer adsorption. Different from the buildup of

such multilayers on macroscopically flat substrates,

Caruso et al. (9) developed a novel way for the pro-

duction of core-shell materials of given size, topol-

ogy, and composition (Fig. 2) and subsequent

removal of the core by either dissolution to produce

hollow particles or decomposition to give hollow

polymer shells.

The fabrication of hollow inorganic silica and

inorganic-hybrid spheres can be achieved through

the colloid templated electrostatic layer-by-layer self-

assembly of silica nanoparticle (SiO2)–polymer

multilayers, followed by the removal of the templated

core and, optionally, the polymer (Fig. 2). Polystyrene

latex particles of 640 nm in diameter have been used

as templates, and SiO2 particles of approximately

25 nm in diameter used as the coating nanoparticles.

These nanoparticles electrostatically self-assemble

onto the linear cationic polymer poly(diallyldi-

methylammonium chloride) (PDADMAC) (16). The

186

Kong et al.

wall thickness of the hollow spheres and ultimately

their shape and stability are dependent on the

number of SiO2-PDADMAC layer deposition cycles

(Fig. 2, steps 2 and 3).

It has been demonstrated that the layer-by-layer

self-assembly technique, when applied to produce

composite SiO2 nanoparticle-polymer multilayers on

colloids, coupled with removal of the core (and

optionally the polymer), provides a successful path-

way for fabricating inorganic and inorganic-hybrid

hollow spheres in the submicrometer-to-micrometer

size range.

There are a number of important advantages to

using this method to fabricate hollow spheres. Firstly,

the thickness of the hollow sphere walls can be

readily controlled by varying the number of depos-

ition cycles. Secondly, the size and shape of the

spheres produced are determined by the dimensions

of the templating colloid employed. Thirdly, the

method is generally applicable to a wide variety of

charged inorganic particles, thereby making possible

the production of various inorganic (such as TiO2 and

ZrO2) and composite (magnetic nanoparticle and

SiO2 or TiO2) hollow spheres.

Polymeradsorption (2) SiO2

(1) (3) PDADMACColloidalparticle (2), (3) …

Calcination Exposure toSolvent

HollowInorganic-Hybrid Spheres

Multilayer-CoatedParticles

Hollow Silica Sphere

Fig. 2. Illustration of procedures for preparing inorganic and hybrid hollow spheres. The scheme is shown for polystyrene

latex particles. PDADMAC, poly (diallyldimethylammonium chloride). (Reprinted with permission from Caruso et al.

Science 1998: 282: 1111–1114 (9); copyright (1998) AAAS).

Fig. 1. Supermolecular nanostruc-

tures with well defined shapes and

sizes. (Reprinted with permission

from Stupp et al. Science 1997: 276:

384–389 (76); copyright (1997)

AAAS).

187

Nanotechnology and periodontics

Core-shell nanostructures

Core-shell particles have attracted much research

attention in recent years because of the great

potential for protection, modification, and functional

properties of the core particles with suitable shell

materials to achieve specific physical (optical,

mechanic, and magnetic), chemical (reaction activity

and catalytic), and biological performance (curing,

drug delivery and release) (11, 67). Core-shell parti-

cles possessing complete and smooth shells can be

prepared with various technologies, for example, by

introducing nanoparticles of desired shell material,

prepared with the reverse micelle process, onto the

core particle surface via layer-by-layer electrostatic

adsorption, hydrophilic and hydrophobic interac-

tions, and subsequent sintering (11).

There are many advantages to such a synthetic

approach (67). The confined cubic micrometer or

submicrometer volume enables one to carry out

chemical synthesis in a highly organized solvent

structure, which can result in new composite nano-

materials that are impossible or difficult to synthesize

in conventional bulk media. This process also allows

the in situ fabrication of nanoreactors filled with

catalytically active components, and it also dimin-

ishes the effect of overconcentration and overheating

in the reaction vessel when reagents are added.

Through such processes it is possible to tailor dif-

ferent functionalities to the microenvironments as a

result of synthesis in one action, thus permiting

modeling and mimicking of biochemical processes in

living cells and their compartments by means of

nanoscale chemistry.

A biomimetic synthesis of the most typical apatite –

calcium hydroxyapatite, Ca10(PO4)6(OH)2 – exclu-

sively inside polyallylamine hydrochloride ⁄ poly(styrene sulfonate) (PSS) polyelectrolyte capsules has

been described and illustrated in Fig. 3a (68). The

thickness and particle size of the YF3 layer formed by

adding F– loaded capsules to a water solution con-

taining Y3+ ions depends greatly on the concentration

of yttrium salt in solution. For example, a 50–100 nm

layer made up from 7–10 nm particles is observed for

high Y3+ concentration, whereas separate agglomer-

ates attached to the inner wall are formed at low Y3+

concentrations (< 10)6 M). It has been reported that

the mechanical stability of such composite structures

is higher than that noted for the initial polyelectrolyte

structures (67).

Shchukin et al. also reported a method (Fig. 3b)

(66) in which entrapped PSS or polyaniline in emer-

aldine, form molecules which act as electron donors

for photoinduced silver reduction both inside and

(a)

Mn+ MAn

(Y3+,Ca2+)

Men+

(F-, PO43-)

An-

PAH/cit An-

CBA

(b)

El. Donor (PSS, dextran, polyaniline) UV/vis

(TiO3)

AgNO3

(Cu2+, Pd2+)

A CB

Fig. 3. Schematic of (a) the ion exchange nanosynthesis inside polyelectrolyte capsule (68); (b) photoinduced synthetic

reactions inside polyelectrolyte capsule (66). PAH, polyallylamine hydrochloride; PSS, polystyrenesulfonate.

188

Kong et al.

outside the capsule shell. It is envisaged that the

nanomaterials synthesized inside the confined cubic

micrometer and the submicrometer volume have a

number of advantages including:

• a high catalytic activity due to the nanoparticle

morphology and large surface area;

• a high stability of nanoparticles against aggrega-

tion;

• a microreactor shell that protects the nanomate-

rials from impurities;

• the formation of metastable and amorphous

modification;

• the possibility to carry out multistep synthesis

and to obtain composite, hierarchically architec-

tured nanomaterials (67).

Polyvinylalcohol ⁄ silicacomposites

The layer-by-layer self-assembly method as des-

cribed by Decher (16) has been applied to poly-

vinylalcohol ⁄ silica (PVA ⁄ SiO2), the result being a

novel nanocomposite (55, 56). The schematic repre-

sentation of this self-assembly monolayer nanocom-

posite process is shown in Fig. 4 (56). Firstly, the SiO2

nanoparticles are negatively charged and these act as

templates to adsorb positively charged polyallylam-

ine hydrochloride molecular chains through electro-

static adsorptive interaction. Polyvinylalcohol

molecular chains are then assembled on the surface

of SiO2 nanoparticles through hydrogen bonding

between the hydroxy groups of the polyvinylalcohol

and amino groups of the polyallylamine hydrochlo-

ride. Finally, the treated SiO2 nanoparticles are uni-

formly dispersed in bulk polyvinylalcohol matrix,

which is cast in a polytetrafluorethylene Petri dish,

and dried in a vacuum oven to obtain polyvinylal-

cohol ⁄ SiO2 nanocomposite film.

The SiO2 nanoparticles are found to be homogen-

eously distributed throughout the polyvinylalcohol

matrices as nanoclusters with an average diameter

ranging from 15 nm to 240 nm depending on the

SiO2 contents. The SiO2 nanoparticles are not

assembled in the composite as individual particles

but as clusters of particles. The number of nanopar-

ticles in a cluster depends on the amount of SiO2

added. As the average diameter of the SiO2

nanoparticles employed is just 14 nm, a complete

polyallylamine hydrochloride or polyvinylalcohol

molecular chain is longer than the circumference of a

single particle and is able to assemble more than one

Fig. 4. The schematic of PVA ⁄ SiO2 nanocomposite process (55, 56). PAH: polyallylamine hydrochloride; PVA: poly-

vinylalcohol.

189

Nanotechnology and periodontics

SiO2 nanoparticle. The average size is less than 30 nm

when the SiO2 content is below 5 wt%, indicating

that a SiO2 cluster has only (quite a few) primary

nanoparticles. However, at SiO2 contents of 10 wt%

and 15 wt%, the size of the SiO2 clusters is 100 nm

and 240 nm, respectively, which suggests that when

the SiO2 content is higher than a certain level,

nanoparticles will aggregate.

The nonisothermal crystallization behavior and

kinetics of the PVA ⁄ SiO2 nanocomposites have been

investigated and compared to those of pure polyvi-

nylalcohol (55). The degree of crystallinity (Xc), peak

crystallization temperature (Tp), half time of crystal-

lization (t1 ⁄ 2), and Ozawa exponent (m) on depends

heavily on the SiO2 content and cooling rate. The

crystallization activation energy (E), calculated with

the Kissinger model, is markedly lower when a small

amount of SiO2 is added. This then gradually

increases and finally becomes higher than that of the

pure polyvinylalcohol when there is more than 10

wt% SiO2 in the composite.

The mechanical properties of the polyvinylalco-

hol ⁄ SiO2 composite has also been improved signifi-

cantly over those of pure polyvinylalcohol (Fig. 5).

Polyvinylalcohol, as a plastic, shows a typical curve

having a yield point at 3.4% strain with a peak stress

of 65.7 MPa. A change of the fracture mechanisms is

observed, from the ductile fracture with a yield point

for composites with low SiO2 (0.5–5 wt%) to the

brittle fracture without yielding for high SiO2 com-

posites (10 wt% and 15 wt%). When 15 wt% SiO2 is

added into polyvinylalcohol matrix, the composite

becomes very brittle.

Dental tissues and nanostructures

Although tooth enamel, cementum, and bone are

composed of organized assemblies of carbonated

apatite crystals, enamel is unusual in that it does not

contain collagen and does not remodel. Self-assem-

bly of amelogenin protein into nanospheres has been

recognized as a key factor in controlling the oriented

and elongated growth of carbonated apatite crystals

during dental enamel biomineralization. Du et al.

reported (18) the in vitro formation of birefringent

microribbon structures that were generated through

the supramolecular assembly of amelogenin nano-

spheres. These microribbons have diffraction pat-

terns that indicate a periodic structure of crystalline

units along the long axis. The growth of apatite

crystals oriented along the c axis and parallel to the

long axes of the microribbons was observed in vitro.

The linear arrays (chains) of nanospheres observed as

intermediate states before the microribbon formation

give an important indication as to the function of

amelogenin in controlling the oriented growth of

apatite crystals during enamel mineralization. Whe-

ther similar processes involving supramolecular

assembly of nanostructures might be involved in

other mineralized tissues such as bone or cementum

remains to be established.

0

50

100

150

200

0 5 10 15 20 25

Strain (%)

rtS

ess

aP

M()

PVA

N-0.5

N-2

N-5

N-10

N-15

Fig. 5. Strain–stress relationship

of PVA and PVA ⁄ SiO2 nanocom-

posites. PVA, polyvinylalcohol.

190

Kong et al.

Direct visualization by transmission electron

microscopy, scanning electron microscopy, and

atomic force microscopy of microribbon, developed

by Du et al. (18), revealed that the larger aggregates

were the result of further association of nanospheres

in a linear arrangement (Fig. 6). Those subunits inside

a nanosphere had a quasispherical appearance, 4–

8 nm in diameter, consistent with the dynamic light

scattering measurement of amelogenin oligomers.

The bridging between nanospheres was observed by

thin threads (white arrow in the inset), the width of

which was on the same scale as that of the subunits.

The fusion of adjacent nanospheres is manifested as a

sharing of subunits (black arrow in the inset). The

linear alignment of several subunits was evident in-

side some nanospheres (upper inset). The further

association of nanospheres led to higher levels of

hierarchical structures. Nanosphere chains were also

observed by transmission electron microscopy as an

intermediate state before the formation of microrib-

bons (Fig. 6A). The nanochain structures were also

observed in the microribbons by atomic force micr-

oscopy (Fig. 6B.C). The size range of the nanospheres

(10–20 nm in diameter) in the microribbon was

consistent with the lower limit from dynamic light

scattering measurement in solution. Nanochains

more than 100 nm long were aligned roughly parallel

to the long axis of the ribbons (Fig. 6C).

Nanorods/nanofibers/nanotubesas dental materials

Nanoparticles are being developed for a host of bio-

medical and biotechnological applications including

drug delivery, enzyme immobilization and DNA

transfection. Spherical nanoparticles are typically

used for such applications as discussed above, but

this only reflects the fact that spheres are easier to

make than other shapes (36). Nanofibers that are less

than 100 nm in diameter, including nanorods (13, 23,

54), nanoplatelets, nanotubes (15, 57, 84), nanofibrils,

and quantum wires, are other major nanomaterials

being widely explored for various applications, of

which management of the periodontal diseases could

be a prime target.

Nanorods

The application of surfactants as reverse micelles or

microemulsions for the synthesis and self-assembly

of nanoscale structures is one of the most widely

adopted methods in nanotechnology. Chen et al. (13)

took advantage of these latest developments in the

area of nanotechnology to mimick the natural bio-

mineralization process to create the hardest tissue in

the human body, dental enamel, by using highly

organized microarchitectural units of nanorod-like

calcium hydroxyapatite crystals arranged roughly

parallel to each other. As detailed above, fully devel-

oped mature dental enamel is made of enamel

prisms, highly organized microarchitectural units,

which consist of bundles of nanorod-like calcium

hydroxyapatite crystals arranged roughly parallel to

each other. This structure spans the entire enamel

thickness and is likely to play an important role in

determining the unique physicochemical properties

of the enamel (12, 13).

Nanotubes

Kolhi & Martin (36) indicated that micro- and nano-

tube structures that resemble tiny drinking straws are

alternatives and may offer advantages over spherical

nanoparticles for some applications. Examples of

nanotubes include organosilicon polymer nanotubes,

self-assembling lipid microtubes, fullerene carbon

nanotubes, template-synthesized nanotubes, and

peptide nanotubes. They offer some interesting

advantages relative to spherical nanoparticles for

biotechnological applications (36). For example, the

large inner volumes (relative to the dimensions of

the tube) can be filled with any desired chemical or

biochemical species ranging in size from proteins to

small molecules (40). In addition, the distinct inner

and outer surfaces can be differentially functionalized

chemically or biochemically (47). The open mouths

may also make the inner surface accessible and make

incorporation of species within the tubes particularly

easy.

Many different approaches to making micro- and

nanotubes have been used and include:

• molecular self-assembly (8) by accurate and

controlled application of intermolecular forces;

• template-synthesized nanotubes – a general

approach for preparing nanomaterials that entails

synthesis or deposition of the desired material

within the cylindrical and monodisperse pores of

a nanopore membrane or other solids;

• in-pore polymerization to make polymeric nano-

tubes;

• electroless deposition to make metal nanotubes;

• sol-gel chemistry to make nanotubes composed

of silica and other inorganic materials.

191

Nanotechnology and periodontics

Fig. 6. Imaging of subunits and linear chains of nano-

spheres formed during amelogenin supramolecular

assembly. A) Transmission electron micrographs of the

linear arrays of amelogenin nanospheres collected. B)

Atomic force microscopy phase image of the surface of an

amelogenin ribbon. C) Back-transform with the frequen-

cies within the box in (B). (Reprinted with permission

from Du et al. Science 2005: 307: 1450–1454 (18); copy-

right (2005) AAAS).

192

Kong et al.

TiO2 nanotube arrays and associated nanostruc-

tures have recently been developed (50). Although

developed as a photocatalyst and for other sensor

applications, these structures may also be useful as

an incorporated nanostructure to titanium implant

metals for orthopaedic and dental implants. Vertic-

ally aligned nanotube arrays of titanium oxide can be

fabricated on the surface of titanium substrates by

anodization. During in vitro immersion in a simula-

ted body fluid, the nanoscale sodium titanate can

induce nucleation and growth of nano-dimensioned

hydroxyapatite. The kinetics of hydroxyapatite for-

mation appears to be significantly accelerated by the

presence of such nanostructures (50).

Nanomaterials for periodontal drugdelivery

Nanomaterials are of interest from a fundamental

point of view because the properties of a material

(e.g. melting point, electronic properties, optical

properties) change when the size of the particles that

make up the material becomes nanoscopic. With new

properties, come new opportunities for technological

and commercial development, and applications of

nanoparticles have been demonstrated or proposed

in areas as diverse as microelectronics, coatings

and paints, and biotechnology (36). From these

applications has come the development of nano-

pharmaceuticals, nanosensors, nanoswitches, and

nanodelivery systems. Each of these has considerable

significance in the field of local, or targeted, drug

delivery.

Recently, Pinon-Segundo et al. (59) produced and

characterized triclosan-loaded nanoparticles by the

emulsification–diffusion process, in an attempt to

obtain a novel delivery system adequate for the

treatment of periodontal disease. The nanoparticles

were prepared using poly(D,L-lactide-coglycolide),

poly(D,L-lactide) and cellulose acetate phthalate.

Poly(vinyl alcohol) was used as stabilizer. Batches

were prepared with different amounts of triclosan in

order to evaluate the influence of the drug on nano-

particle properties. Solid nanoparticles of less than

500 nm in diameter were obtained. These triclosan-

nanoparticles behave as a homogeneous polymer

matrix-type delivery system, with the drug (triclosan)

molecularly dispersed. Release kinetics indicates that

the depletion zone moves to the center of the device

as the drug is released. This behavior suggests that

the diffusion is the controlling factor of the release.

A preliminary in vivo study using these nanopar-

ticles has been performed in dogs with only the gin-

gival index (GI) and bleeding on probing (bleeding on

probing) being determined (59). With respect to the

gingival index (GI), at days 1 and 8, it was found that

a severe inflammation was detected in control and

experimental sites (GI ¼ 3). It was concluded that

triclosan nanoparticles were able to effect a reduction

of the inflammation of the experimental sites.

This study has specifically tackled periodontal

management; however, nanomaterials including

hollow spheres (9), core-shell structure (67), nano-

tubes and nanocomposite (55) have been widely

explored for controlled drug release (36, 38, 41, 49,

70, 78, 79). It is conceivable that all of these

materials could be developed for periodontal drug

delivery devices in the future. Drugs can be incor-

porated into nanospheres composed of a biode-

gradable polymer, and this allows for timed release

of the drug as the nanospheres degrade (39, 77).

This also allows for site-specific drug delivery.

A good example of how this technology might

be developed is the recent development of Arestin�

in which tetracycline is incorporated into micro-

spheres for drug delivery by local means to a

periodontal pocket (53).

Nanomaterials for periodontal tissueengineering

Currently, tissue engineering concepts for perio-

dontal regeneration are focused on the utilization

of synthetic scaffolds for cell delivery purposes (4).

Although the utilization of such systems offers

promise, it is very likely that the next generation of

materials will rely heavily on nanotechnology and

its potential to produce nonbiologic self-assembling

systems for tissue engineering purposes (5). As

detailed above, self-assembling systems for biologic

systems are those which automatically undergo

prespecified assemblies much in line with known

biologic systems associated with cells and tissues.

Using these principles, it is possible to construct

systems on a nano-, micro- or even macro-scale.

Current materials available for such constructs are

metals, ceramics, polymers, and even composite

materials, the like of which have not yet been

developed. The clinical utility of these nano-con-

structed self-assembling materials is their capacity

to be developed into nanodomains or nanophases,

leading to unique nanobuilding blocks with inbuilt

nanocontrol and nanodelivery capabilities. For tis-

sue engineering purposes the potential of nano-

technology is limited only by our imagination. Our

present capacity to create polymer scaffolds for cell

193

Nanotechnology and periodontics

seeding, growth factor delivery and tissue engin-

eering purposes is well recognized. In the future

these processes may well be manipulated via

nanodevices implanted to sites of tissue damage.

Concluding comments

Although the achievement of the goal of complete

regeneration of the periodontal tissues (cementum,

periodontal ligament and bone) for periodontal

management may not be possible for many years (4,

74), recent developments in nanomaterials and

nanotechnology have provided a promising insight

into the commercial applications of nanomaterials in

the management of periodontal diseases (59). A large

number of materials scientists have devoted their

efforts to the development of new nanomaterials;

however, a need exists for them to collaborate more

closely with dentists and dental scientists.

While current work is focused on the recent

development particularly of nanoparticles (10, 11,

34, 36, 67, 82) and nanotubes (15, 26, 50, 54) for

periodontal management, the materials developed

from them such as the hollow nanospheres (9),

core-shell structures (67), nanocomposites (55, 56),

nanoporous materials (61, 63, 75), and nanomem-

branes (26, 31, 60) will play a growing role in

materials development for the dental industry.

Although many studies have been published con-

cerning nanocomposite (48, 51, 55, 71, 82) and

nanoporous materials (1, 64, 83) it will become of

increasing importance to specifically develop

nanomaterials for the management of periodontal

diseases. It is envisaged that this trend will be

further improved in the future as more and more

nanotechnologies are commercially explored.

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