Geckeler K.E., Nishide H. (Eds.) Advanced Nanomaterials

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16.2 Tissue Engineering and Regeneration 529

mimic those of natural bone, is a goal to be pursued. It is well known that natural

bone consists of nanosized, plate - like crystals of HAp grown in intimate contact

with an organic matrix which is rich in collagen ﬁ bers. One novel approach to

fabricating nanocomposite bone grafts, using strategies found in Nature, has

recently received much attention and is perceived to be beneﬁ cial over conven-

tional methods. A variety of production methods have been employed for the

formation of collagen – HAp composite gels, ﬁ lms, collagen - coated ceramics,

ceramic - coated collagen matrices and composite scaffolds for spine and hard

tissue repair [17] .

Stem cells are cells from an embryo, fetus, or adult that have the ability to repro-

duce for long periods, and can also give rise to specialized cells that comprise the

tissues and organs of the body. When implanted onto immunodeﬁ cient mice,

stem cells were shown to combine with mineralized 3 - D scaffolds to form a highly

vascularized bone tissue. Cultured cell – bioceramic composites can be used to treat

defects across the bone diaphysis, with excellent integration of the ceramic scaffold

with bone, and a good functional recovery [18] . Excellent innovative studies with

nanobioceramics are currently in progress, and clinical applications are becoming

relatively common.

Vago and coworkers [19] have introduced a novel 3 - D biomatrix obtained from

the marine hydrocoral Millepora dichotoma as a scaffold for hard - tissue engineer-

ing. M. dichotoma was biofabricated under both ﬁ eld and laboratory conditions,

and 3 - D biomatrices prepared in order to convert mesenchymal stem cell s ( MSC s)

to exemplify an osteoblastic phenotype. The effect of the biomatrices on the pro-

liferation and differentiation of MSCs was then examined at 2, 3, 4, 7, 10, 14, 21,

28, and 42 days. The investigations included light microscopy, scanning electron

microscopy ( SEM ) and energy dispersive spectroscopy ( EDS ), in addition to moni-

toring calcium incorporation into newly formed tissue (with Alizarin red staining),

bone nodule formation (von Kossa staining), fat aggregate formation (oil red O

staining), collagen type I immunoﬂ uorescence, DNA concentrations, alkaline

phosphatase ( ALP ) activity, and osteocalcin concentrations. The MSCs seeded onto

M. dichotoma biomatrices showed higher levels of calcium and phosphate incor-

poration, and higher type I collagen levels, than did control Porites lutea biomatri-

ces. In addition, the ALP activity revealed that those MSCs seeded on M. dichotoma

biomatrices were highly osteogenic compared to those on control biomatrices. The

osteocalcin content of MSCs seeded on M. dichotoma remained constant for up to

two weeks, before surpassing that of seeded P. lutea biomatrices after 28 days. The

investigators reported that M. dichotoma biomatrices enhanced the differentiation

of MSCs into osteoblasts, and hence showed excellent potential as bioscaffolding

for hard - tissue engineering.

As emerging areas, both tissue and implant engineering are evolving to address

the shortage of human tissue and organs. Feasible and productive strategies have

been aimed at combining a relatively traditional approach, such as bioceramic

implants, with the acquired knowledge applied to the ﬁ eld of cell growth and dif-

ferentiation of osteogenic cells. The core of the tissue engineering and regenerative

medicine is the fabrication of scaffolds, in which a given cell population is seeded,

530 16 Nanoceramics for Medical Applications

proliferated, and differentiated with the introduction of functional cell types from

many different sources [20] .

Nanostructured materials and their modiﬁ ed forms offer some attractive pos-

sibilities in the ﬁ elds of tissue and implant engineering, taking advantage of the

combined use of living cells and 3 - D ceramic scaffolds (Figure 16.2 ) to deliver vital

cells to the damaged site of the patient. Recently, bone - like nanostructure scaffolds

have been developed using the technology of composites to imitate natural bone

in bone - tissue engineering [21] .

The results of recent studies have suggested that bone marrow stromal cells might

be a potential source of osteoblasts and chondrocytes, and can be used to regener-

ate damaged tissues using a tissue - engineering approach. However, these strate-

gies require the use of an appropriate scaffold architecture that can support the

formation de novo of bone and/or cartilage tissue, as in the case of osteochondral

defects. Oliveira et al . [14, 22] developed a novel hydroxyapatite/chitosan ( HAp/

CS ) bilayered scaffold by combining a sintering and a freeze - drying technique,

aiming to show the potential of such scaffolds to be used in tissue engineering

for osteochondral defects. Subsequently, in vitro (Phase 1) cell culture studies were

carried out to evaluate the capacity of the HAp and CS layers to separately support

the growth and differentiation of goat bone marrow stromal cell s ( GBMC s) into

osteoblasts and chondrocytes, respectively. The data showed not only that the

GBMCs were able to adhere and proliferate but also that the constructs exhibited

a great potential for use in tissue - engineering strategies, leading to the formation

of adequate tissue substitutes for the regeneration of osteochondral defects.

The effects of surface chemistry modiﬁ cations of titanium alloy (Ti - 6Al - 4V) with

zinc, magnesium, or alkoxide - derived nanocrystalline carbonate hydroxyapatite

( CHAp ) on the regulation of key intracellular signaling proteins in human bone -

derived cell s ( HBDC s) cultured on these modiﬁ ed Ti - 6Al - 4V surfaces, have been

investigated in Australia by Zreiqat et al . [23] . The surface modiﬁ cation with

nanocrystalline CHAp was shown to contribute to successful osteoblast function

and differentiation at the skeletal tissue – device interface.

The role of gene therapy in aiding wound healing and treating various diseases

or defects has become increasingly important in the ﬁ eld of tissue engineering.

The use of 3 - D scaffolds in gene delivery has emerged as a popular and necessary

delivery vehicle for obtaining controlled gene delivery. Ko et al . [24] described the

techniques to synthesize composite scaffolds by combining natural polymers such

as agarose and alginate with calcium phosphate ( CaP ). Alginate has been used

extensively in various applications such as cell encapsulation seeding, gene deliv-

ery, and antibody or growth factor entrapment and release, while agarose has been

used as a scaffold involved in cartilage repair. The incorporation of CaP into the

agarose or alginate hydrogels was performed in situ . Ko et al . concluded that, by

incorporating CaP into the agarose or alginate hydrogel, they were able to synthe-

size a scaffold that was mechanically strong and chemically suitable for use as a

gene - delivery vehicle in tissue engineering.

For many implants, a sustained and controlled release of antibacterial agents

into the wound site is desirable for combating infection. A further advantage of

nanostructured sol – gel - derived glasses is that silver, which is known to have anti-

16.2 Tissue Engineering and Regeneration 531

bacterial properties, can be incorporated into the glass composition. The addition

of silver ions to bioactive glasses has also been investigated by Jones et al . [25] , for

the production of glasses with bactericidal properties. A bioactive glass scaffold

containing 2 mol% silver was shown to release silver ions at a rate shown previ-

ously to be bactericidal in, but not cytotoxic to, bone cells.

16.2.2

Liposomes

Liposomes are the most clinically established nanometer - scale systems currently

used to deliver nontoxic and antifungal drugs, genes, and vaccines; they are also

being used as imaging agents. Liposomes consist of a single layer, or multiple

concentric lipid bilayers, that encapsulate an aqueous compartment. The outstand-

ing clinical proﬁ le of liposomes, compared to other delivery systems, is based on

their biocompatibility, biodegradability, reduced toxicity, and capacity for size and

surface manipulations [26] .

Nanometer - sized particles, such as superparamagnetic iron oxides, semicon-

ducting nanocrystals, silica nanoparticles, and calcium phosphate, each possess

novel functions that include unique magnetic, optical, therapeutic, and medical

properties. The encapsulation of these nanoparticles within liposomes may lead

to an enhanced nanoparticle hydrophilicity, stability in plasma, and an overall

improvement in their biocompatibility [26 – 28] . Furthermore, by utilizing the

ability of liposomes to carry hydrophilic and hydrophobic moieties, combinatory

therapy/imaging modalities can be achieved by incorporating therapeutics and

diagnostic agents into a single liposome - delivery system [26] .

Semiconductor nanocrystals, known as quantum dot s ( QD s) are ﬂ uorescent

nanoparticles with a diameter in the range of 1 to 10 nm. QDs offer distinct spec-

troﬂ uorometric advantages over traditional ﬂ uorescent organic molecules, with

typical ﬂ uorescence characteristics 10 to 20 - fold brighter than conventional dyes.

QDs also exhibit a greater photostability, a broad excitation wavelength range, a

size - tunable spectrum, and a narrow and symmetric emission spectrum. On the

basis of these photophysical characteristics QDs are currently being investigated

as potential imaging agents, primarily in ﬂ uorescence - based diagnostic applica-

tions [26] .

The self - assembly of organized nanoscopic structures has been the subject of

much interest in both colloidal and nanomaterials science. Indeed, some recent

studies have shown that nanoscale liposomes can be used as a nanoscale template

for the deposition of silica, so as to create a hollow silica nanoshell. These silicate

materials have been used to encapsulate ﬂ uorescent dyes, enzymes, polymer par-

ticles, and liquids [27] . Moreover, the liposome – silica nanoparticle hybrid systems

thus formed can be used in the design of biosensors, whereby the physical char-

acteristics of silica can be matched with the biocompatibility and pharmaceutical

and pharmacodynamic properties of liposomes [28] .

Calcium phosphate - based hybrid nanoparticles have shown great promise as

candidates for drug delivery and bone regeneration systems, based on the excellent

biocompatibility of calcium phosphate [29] . Recently, hydroxyapatite - coated

532 16 Nanoceramics for Medical Applications

liposome s ( HACL s) were successfully manufactured and ﬁ lled with a model

hydrophobic (lipophilic) drug, namely indomethacin ( IMC ) [29] . In this process,

the HAp layer was precipitated onto the liposomes, the aim being to provide the

HACL with two functions: (i) that the inner core liposome provides a sustained

drug release; and (ii) that the outer HAp layer provides the osteoconductivity for

bone cells. The liposomes were formed from 1,2 - dimyristoyl - sn - glycero - 3 - phos-

phate ( DMPA ) and 1,2 - dimyristoyl - sn - glycero - 3 - phosphocholine ( DMPC ). The

results reported by Xu et al . [29] indicated that precipitating HAp onto the liposome

reduced the release rate of IMC compared to uncoated liposomes. In fact, under

the conditions used, the 5 h period required to release 70% of the IMC from the

liposomes was extended to 20 h when the liposomes were coated with HAp.

Perhaps, more importantly, IMC release from the uncoated liposomes occurred

more rapidly at pH 7.4 than at pH 4, whereas the HAp coating reduced the release

rate at pH 7.4 compared to that at pH 4. Based on these ﬁ ndings, Xu et al .

suggested that this effect might open up the possibility of creating “ smart ”

(pH - controlled) targeted drug delivery devices.

When Hang et al . [30] used liposome - coated HAp and tricalcium phosphate as

bone implants in the mandibular bony defect of miniature swine, they found the

liposome - coated materials to be biocompatible. Moreover, the clinical endpoint

was enhanced compared to that in the absence of liposomes. It was hypothesized

that coating hydroxyapatite and tricalcium phosphate with negatively charged

liposomes might improve the nucleation process for new bone formation. In

experiments conducted in miniature swine, artiﬁ cial bony defects on one side were

implanted with either HAp - coated or tricalcium phosphate - coated liposomes,

while defects on the other side served as controls. Histology and radiography

performed at three and six weeks after surgery showed the coated liposome materi-

als to be biocompatible. At three weeks, the implant material was surrounded by

dense connective tissues, whilst by six weeks, new bone formation was visible near

the implanted material. Liposomes immobilized in agarose gel and implanted in

the defects also showed new bony bridge formation.

16.3

Nanohydroxyapatite Powders for Medical Applications

Bone mineral is composed of nanocrystals or, more accurately, nanoplatelets

which originally were described as HAp, and similar to the mineral dahllite . Today,

it is agreed that bone apatite may be better described as CHAp, and approximated

by the formula (Ca,Mg,Na)

(PO

)

(OH)

. The composition of commercial

CHAp is similar to that of bone mineral apatite. Bone pore sizes range from 1 to

100 nm in normal cortical bone, and from 200 to 400 nm in trabecular bone tissue,

with the pores being interconnected.

Orthopedic implants used mainly for joint replacement and fracture ﬁ xation

include metallic (cobalt chromium or titanium alloys) implants, screws, plates

and nails, and their various permutations and combinations. The most important

16.3 Nanohydroxyapatite Powders for Medical Applications 533

parameters for these implants are that they have the necessary wear resistance,

allow for an adequate attachment to bone, and display the required strength,

ductility, and elasticity. At a bone - implant – load - carrying interface, the greater the

implant material stiffness, the greater load it can carry, compared to the sur-

rounding tissues. This imbalance in load, which is known as stress shielding , can

cause the bone tissue to be resorbed. An implant that is too rigid may also

increase the likelihood of bone fracture, as the bone becomes osteoporotic

(thinned) due to the excessive protection generated by the stress - shielding effect

of the implant.

Macro - textured implants nanocoated with calcium phosphate and possessing the

appropriate bioactivity characteristics, bonding ability, and design, may be the

answer to this serious problem. A range of new nanomaterial production compa-

nies are in the process of applying this new technology in orthopedic, cardiovas-

cular, and dental implants.

Nanotechnology has opened up novel techniques for the production of bone - like

synthetic nanopowders and coatings of HAp. Indeed, the availability of HAp nano-

particles has opened up new opportunities for the design of superior biocompat-

ible coatings for implants, and the development of high - strength orthopedic and

dental nanocomposites.

Although, bone - like HAp nanopowders and nanoplatelets (Figure 16.3 ) can be

synthesized by a range of production methods, one very promising approach is

to synthesize these materials via a sol – gel solution. The results of earlier studies

have shown that, while biphasic sol – gel HAp products are easily synthesized,

monophasic HAp powders and coatings are more difﬁ cult to produce. Many

companies have successfully synthesized HAp nanoparticles with diameters in

the range of 15 to 20 nm, and with HAp coatings 70 nm thick (Nanocoatings Pty.

Ltd., Australia). The nanoparticles and nanoplatelets of HAp provide excellent

bioactivity for integration into bone, which arises from their very high surface

areas [31, 32] .

Figure 16.3 Nanocrystalline carbonate apatite platelets formed by a sol – gel process.

534 16 Nanoceramics for Medical Applications

Several new production and surface - modiﬁ cation techniques, including some

sol – gel techniques, chemical vapor deposition ( CVD ), and plasma spray, have

resulted in bonds with an excellent adhesive strength between the HAp and the

substrate material, while others may be poor (e.g., electrophoretic deposition,

various solution dip - coating systems, thermal spray). Currently, several companies

and research groups are producing nanocomposites (e.g., NanoCoatings Pty Ltd,

Australia; Mitsubishi Materials; ApaTech Ltd; Dentsply International; BioMet Int.;

Wyeth BioPhamia; and Medtronic Sofamor Danek) that incorporate the macropar-

ticles and nanoparticles of HAp and organic and biogenic materials (e.g., polyeth-

ylene, synthetic peptides and collagen, growth factors). Such a combination

provides mechanical strength that is not achievable by using nanoparticles alone.

In addition, for some of these materials an enhanced bioactivity and mechanical

properties have been reported in orthopedic and dental applications, such as bone

cements and dental ﬁ llings [33] .

Saiz and coworkers [34] have focused on the sintering of porous HAp scaffolds

fabricated using two techniques based on manipulation of the HAp slurries,

namely inﬁ ltration of the polymer foams and robocasting :

• The ﬁ rst method involves the inﬁ ltration of a polymer sponge with a ceramic

slurry until the inner polymer walls are completely coated by the ceramic

powders. Subsequently, the sample is ﬁ red to remove the polymer and form a

ceramic skeleton that is strengthened by sintering at high temperature.

• The second technique involves the use of computer - driven rapid prototyping

techniques to produce porous ceramic with anisotropic microstructures. This

so - called “ robocasting ” is a simple technique used to produce porous ceramic

parts with complex shapes. In robocasting, a ceramic ink is extruded through a

thin nozzle to build a part layer - by - layer, following a computer design. Sintering

in air at temperatures ranging between 1100 ° C and 1200 ° C yields dense

materials with narrow, grain - sized distributions.

It has been stated that both techniques can be used to fabricate scaffolds with an

adequate pore size capable of promoting bone ingrowth.

Khalyfa and coworkers [35] have developed a powder mixture comprising tetra-

calcium phosphate ( TTCP ) as the reactive component and β - tricalcium phosphate

( β - TCP ) or calcium sulfate as a biodegradable ﬁ ller, which can be printed with an

aqueous citric acid solution. Two post - processing procedures – a sintering and a

polymer inﬁ ltration process – were established to substantially improve the

mechanical properties of the printed devices. Specimens of different shapes and

sizes have been printed to study the usability of the developed powder - binder

systems in the 3 - D printing process; in this way a 3 - D scaffold with a thoroughly

open channel system was produced. The printing of a human cranial segment,

together with all its ﬁ ligree structures, was successfully achieved using both pow-

der - binder systems, based on computed tomography scanning data of a human

cranium. In all cases, the printed objects were strong enough to be handled manu-

ally, without damaging the integrity of the devices. Preliminary examinations on

relevant application properties, including in vitro cytocompatibility testing, indi-

16.4 Nanocoatings and Surface Modiﬁ cations 535

cated that the new powder - binder system represented an efﬁ cient approach to the

creation of patient - speciﬁ c ceramic bone substitutes and scaffolds for bone - tissue

engineering.

Ordered tubular structures with open porosity were created by de Sousa and

Evans [36] by using the microextrusion freeforming of a tubular latticework. The

extrudate was a suspension of ﬁ ne HAp powder in isopropyl alcohol with a

polyvinyl butyral binder. The extruder consisted of a stepper - driven syringe ﬁ tted

with a miniature tube extrusion die. In this way, tubular lattice scaffolds and

microsprings were successfully prepared from crowded ceramic suspensions of

HAp. The lattices were then sintered at 1250 ° C to produce a ceramic that had

potential as a bone scaffold and could accommodate growth promoters in a slow

release form.

16.4

Nanocoatings and Surface Modiﬁ cations

16.4.1

Calcium Phosphate Coatings

When considering an ideal material to replace and mimic bone, synthetic calcium

phosphates are an obvious choice, as they can replicate the structure and composi-

tion of HAp, a bone mineral. However, despite having a similar composition and

chemistry to that of human bone, the mechanical properties of calcium phosphate

are far from being close to those of human bone, which limits their use for load -

bearing applications.

Today ’ s solutions of materials for bone replacement are still far from ideal, with

metallic implants remaining the ﬁ rst choice for load - bearing applications. As all

metallic orthopedic and dental implants are bioinert and do not bond chemically

to bone, the only means of ﬁ xation is by mechanical interlocks, whereby the

implant must be manufactured in such a way that it possesses suitable surface

roughness by micro - and macro - texturing. By increasing the surface roughness,

the surface area is increased and this in turn increases the area of ﬁ xation. Other

current methods for ﬁ xing implants ﬁ rmly in place are the use of screws or bone

cement, which are both used in dental and orthopedic implants.

Most published information on HAp is classiﬁ ed under calcium phosphate, to

which HAp belongs. Therefore, the chemical properties will be viewed from the

standpoint that HAp is calcium phosphate, although it will have different solubility

and reactivities from other phosphates within the physiological environments.

Calcium phosphates are characterized by particular solubilities, such as when

bonding to the surrounding tissues, and their ability to degrade and be replaced

by advancing bone growth. As the calcium phosphate or HAp comes into contact

with body ﬂ uid, its surface ions can be exchanged with those of the aqueous solu-

tion; alternatively, various ions and molecules, such as collagen and proteins, can

be adsorbed onto the surface [31, 32] .

536 16 Nanoceramics for Medical Applications

The goal of calcium phosphate as a bioactive coating is to achieve a rapid biologi-

cal attachment to bone. Biological ﬁ xation is deﬁ ned as the process by which

prosthetic components become ﬁ rmly bonded to the host bone by bone in - growth,

without the use of adhesive or mechanical ﬁ xation.

Coatings offer the possibility of modifying the surface properties of surgical -

grade materials to achieve improvements in performance, reliability, and biocom-

patibility. More recently, techniques such as physical vapor deposition, thermal

and electron beam evaporation, plasma metalorganic chemical vapor deposition

( MOCVD ), electrochemical vapor deposition, thermal or diffusion conversion and

sol – gel processing have been used to produce both macro - and nanocoatings.

HAp - coated implants have demonstrated extensive bone apposition in animal

models. The development of good implant – bone interfacial strength is thought to

be a result of the biological interactions of released calcium and phosphate ions.

Quality HAp - coated implants heal faster and attach more completely to the bone.

The long - term performance of a calcium - phosphate - coated implant depends on

coating properties such as thickness, porosity, phases and crystallinity, implant

surface roughness, and overall design.

In addition to the effects of surface topography and chemistry, thin depositions

of HAp or calcium phosphate crystals on implants were found to accelerate early

bone formation and increase the strength of the bond between implant and bone.

A histologic and histomorphometric evaluation of the implant – bone interface was

carried out by Orsini and coworkers [37] to determine the effects of a novel surface

treatment created by discrete crystalline deposition of nanometer - sized calcium

phosphate particles added to the dual acid - etched surface of dental implants placed

in the human posterior maxilla. The bone – implant contact evaluations indicated

that an increase in osteoconduction along the calcium phosphate - treated surface

occurs during the ﬁ rst two months after implant placement. These authors also

stated that their results suggested that the nanometric deposition of calcium phos-

phate crystals could be clinically advantageous for shortening the implant healing

period, providing earlier ﬁ xation, and minimizing micromotion, thus allowing

earlier loading and restoration of function for implants placed in areas with low -

density bone.

During the past 20 years, four general industrial coating methods have been

adapted for the production of bioactive coatings:

• Spray coating was developed by Ducheyne and colleagues, who used relatively

thick (100 μ m to 2 mm) calcium phosphate coatings for bone in - growth [38] .

• Thick bioglass coating was initiated and developed by Hench and colleagues for

surface bioactivity [39] .

• The “ self - assembly ” of biomimetics by precipitation in a simulated body ﬂ uid

( SBF ) solution [40] .

• Nanocoatings , using a range of methods including dipping in sol – gel HAp

solutions to produce strong and bioactive coatings [31] .

The sol – gel method in particular represents an attractive and versatile method, as

it can be used to produce ceramic coatings from solutions by chemical means. It

16.4 Nanocoatings and Surface Modiﬁ cations 537

is relatively easy to perform, and complex shapes can be coated. It has also been

shown that the nanocrystalline grain structure results in improved mechanical

properties. Sol – gel processing is also unique in that it can be used to produce

different forms, such as powders, platelets, coatings, ﬁ bers, and monoliths of the

same composition, merely by varying the chemistry, viscosity, and a number of

factors of a given solution.

The advantages of the sol – gel technique are numerous: it is of the nanoscale; it

results in a stoichiometric, homogeneous and pure product, owing to mixing on

the molecular scale; high purity can be maintained as grinding can be avoided; it

allows reduced ﬁ ring temperatures due to its small particle sizes with high surface

areas; it has the ability to produce uniform ﬁ ne - grained structures; it allows the

use of different chemical routes; and it is easily applied to complex shapes with a

range of coating techniques, including dip, spin, and spray deposition (Figure

16.4 ). Furthermore, sol – gel coatings have the added advantages that the costs of

precursors are relatively unimportant, owing to the small amounts of materials

required [31] .

The lower processing temperature has another advantage, namely that it avoids

the phase transition ( ∼ 1156 K) observed in titanium - based alloys used for biomedi-

cal devices.

Currently, companies are producing HAp nanoparticles with diameters in the

range of 15 to 20 nm. Various sol – gel routes have been used for the production of

synthetic HAp. A number of studies have been carried out on a range of precur-

sors to produce pure nanocrystalline apatites for medical applications. A coating

thickness in the range of 70 – 90 nm has been reported by some investigators

[31, 32] .

Figure 16.4 Schematic showing the stages of the sol – gel

dipping process and densiﬁ cation stages of nanocrystalline

coating process.

538 16 Nanoceramics for Medical Applications

Ti metal forms a nanoscale sodium titanate hydrogel layer on its surface, when

it is soaked in 5 M NaOH solution at 60 ° C for 24 h. In Japan, a large number of

patients have been reported to receive artiﬁ cial total hip joints of Ti alloy, modiﬁ ed

with titanium beads subjected to NaOH treatments.

16.4.2

Sol – Gel Nanohydroxyapatite and Nanocoated Coralline Apatite

Current bone graft materials are mainly produced from coralline HAp. Due to the

nature of the conversion process, commercial coralline HAp has retained coral or

CaCO

and the structure possesses nanopores within the inter - pore trabeculae,

resulting in high dissolution rates. Under certain conditions, these features reduce

durability and strength, respectively, and are not utilized where high structural

strength is required. To overcome these limitations, a new double - stage conversion

technique was developed by Ben - Nissan and coworkers [23, 31, 32] .

The current technique involves a two - stage application route whereby, in the

ﬁ rst stage, a complete conversion of coral to pure HAp is achieved. In the second

stage, a sol – gel - derived HAp nanocoating is applied directly to cover the meso - and

nanopores within the intra - pore material, while maintaining the large pores for

appropriate bone growth. The process is shown in Figure 16.5 .

The compression and biaxial strengths, fracture toughness, and Young ’ s

modulus were each improved as a result of this unique double treatment. Applica-

tion of the treatment method is expected to result in an enhanced bioactivity due

to the nanograin size – and hence large surface area – that increases the reactivity

of the nanocoating. It is anticipated that this new material could be applied

to load - bearing bone - graft applications where high - strength requirements are

pertinent.

Figure 16.5 Stages of nanocrystalline

hydroxyapatite - coated coralline apatite

formation. (a) An enlarged micrograph of a

coral skeleton spine area that has very sharp

meso - and nanopore platelet regions;

(b) Surface morphological changes of the

coral after conversion to hydroxyapatite with

the hydrothermal method; (c) Stage 2

covering of the mesopores and nanopores

with a nanohydroxyapatite coating.