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Woodhead Publishing Series in Biomaterials

Bone Response to Dental

Implant Materials

Edited by

Adriano Piattelli

AMSTERDAM • BOSTON • CAMBRIDGE • HEIDELBERG

LONDON • NEW YORK • OXFORD • PARIS • SAN DIEGO
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Contents

List of contributors ix

1 Introduction to bone response to dental implant materials 1

V. Perrotti, F. Iaculli, A. Fontana, A. Piattelli, G. Iezzi
1.1 Introduction 1
1.2 Biomaterials 12
1.3 Challenges and further trends 16
Acknowledgment 20
References 20

2 Mechanical modification of dental implants to control bone retention 25

H. Alexander, J. Ricci
2.1 Introduction 25
2.2 The implant as extracellular matrix 26
2.3 Cell attachment 26
2.4 Cell behavior on smooth surfaces 27
2.5 Cell behavior on three-dimensional and roughened surfaces 27
2.6 Mechanisms involved with translation of cell configuration to
differentiation 28
2.7 Using controlled surface configuration to control cell
functiondtissue engineering surfaces 29
2.8 Mechanical basis for bone retention around dental implants 35
2.9 Conclusion 39
References 40

3 Surface modification of dental biomaterials for controlling

bone response 43
I.-S. Yeo
3.1 Bone responses to implant surfaces 44
3.2 Roughening the surface 46
3.3 Application of inorganic elements to implant surfaces 53
3.4 Application of organic compounds to implant surfaces 56
3.5 Concluding remarks 58
References 60
vi Contents

4 Bone response to calcium phosphate coatings for dental implants 65

S. Anil, J. Venkatesan, M.S. Shim, E.P. Chalisserry, S.-K. Kim
4.1 Introduction 65
4.2 The bone implant interface 66
4.3 Methods of calcium phosphate coating 67
4.4 Surface coating and peri-implant wound healing process 71
4.5 Factors influencing the coated implant bone interface 74
4.6 CaP coating as drug delivery system 77
4.7 CaP coating and peri-implantitis 80
4.8 Conclusion 80
References 80

5 Peri-implant biological behavior: clinical and scientific aspects 89

J.E. Maté S

anchez de Val, J.L. Calvo-Guirado, S. Gehrke
5.1 Introduction 89
5.2 Implant features 90
5.3 Implant anatomy 91
5.4 BIC percentage 93
References 96

6 Implant primary stability and occlusion 101

G. Frisardi, C. Murray, P.P. Valentini, E.M. Staderini, F. Frisardi
6.1 Introduction 101
6.2 Press-fit primary stability 102
6.3 NGF primary stability 110
6.4 Neuro-evoked centric relation 117
6.5 Case reports 119
6.6 Conclusions 122
References 123

7 Clinical bone response to dental implant materials 129

O.T. Jensen
7.1 Bone response to dental implants 129
References 136

8 The effect of loading on peri-implant bone: a critical review

of the literature 139
J. Duyck, K. Vandamme
8.1 Introduction 139
8.2 Implant loading prior to osseointegration 140
8.3 Implant loading after osseointegration 147
8.4 Concluding remarks 155
References 156
Contents vii

9 Bone response to decontamination treatments for dental biomaterials 163

J. Diaz-Marcos
9.1 Introduction 163
9.2 Decontamination methods: description and applications 168
9.3 Implant surfaces and bone response after decontamination 172
9.4 Summary and conclusions 177
References 178

10 Anti-resorptive treatment in osteoporosis and their deleterious

effects on maxillary bone metabolism in clinical dentistry 185
D. Soto-Pe~nazola, M. Pe~
narrocha-Diago, J.V. Bag
an-Sebasti
an,
L. Bag
an-Debon
10.1 Introduction 185
10.2 Concept, diagnosis and classification of BP-associated ONJ 186
10.3 BPs, osteonecrosis, and implant dentistry 200
References 204

11 Biocompatibility and cellular response to dental implant materials 211

B. Zavan
11.1 Introduction 211
11.2 Cell lines 212
11.3 Determination of cytotoxicity 213
11.4 Colony formation cytotoxicity test 215
11.5 MTT cytotoxicity test 216
11.6 XTT cytotoxicity test 217
11.7 Ames test 217
11.8 Hemolysis assay 218
11.9 Karyotype analysis 219
11.10 Alternatives in animal testing 219
11.11 The 4 h human patch testdprotocol 222
11.12 Alternative method for dental implant osteointegration 223
11.13 Benefits of non-animal testing 224
References 225

12 Analysis of bone response to dental bone grafts by advanced

physical techniques 229
A. Giuliani
12.1 Introduction: bone response to dental grafts and the problem
of conventional investigating techniques 229
12.2 Synchrotron radiation and advanced physical techniques:
a new approach 231
12.3 X-ray microdiffraction 233
12.4 X-ray microtomography 236
12.5 From micro-CT to HT: the new trends 242
Acknowledgment 244
References 244
viii Contents

13 Acoustic emission and ultrasound for monitoring the bone-implant

interface 247
R.L. Reuben
13.1 Introduction: physical principles of mechanical monitoring
of the bone-implant interface; vibration, ultrasound and
acoustic emission 247
13.2 Vibrational techniques 249
13.3 Conventional ultrasonics 252
13.4 Active and passive acoustic emission 253
13.5 Summary of current state-of-the-art; dental and nondental
implants 256
References 256

14 A new approach for modeling bone response to dental implant

materials 261
A. De Sanctis, S.A. Gattone
14.1 Introduction 261
14.2 The method 261
References 264

Index 265
List of contributors

H. Alexander Orthogen LLC, Springfield, NJ, United States

S. Anil Prince Sattam Bin Abdulaziz University, AlKharj, Saudi Arabia
L. Bag

an-Debon University of Valencia, Valencia, Spain
J.V. Bag

an-Sebasti

an University of Valencia, Valencia, Spain
J.L. Calvo-Guirado Universidad Cat

olica San Antonio (UCAM), Murcia, Spain
E.P. Chalisserry Pukyong National University, Busan, Korea
A. De Sanctis University “G. d’Annunzio” of Chieti-Pescara, Pescara, Italy
J. Diaz-Marcos Scientific and Technological Centers of the University of
Barcelona, Barcelona, Spain
J. Duyck KU Leuven, Leuven, Belgium; U.Z. St. Raphaël, Leuven, Belgium
A. Fontana University “G. d’Annunzio”, Chieti, Italy
G. Frisardi Epoche e Orofacial Pain Centre, Rome, Italy; University of Sassari,
Sassari, Italy
F. Frisardi Epoche e Orofacial Pain Centre, Rome, Italy
S.A. Gattone University “G. d’Annunzio” of Chieti-Pescara, Pescara, Italy
S. Gehrke Universidad Cat

olica San Antonio (UCAM), Murcia, Spain
A. Giuliani Universita Politecnica delle Marche, Ancona, Italy
F. Iaculli University “G. d’Annunzio”, Chieti, Italy
G. Iezzi University “G. d’Annunzio”, Chieti, Italy
O.T. Jensen University of Utah School of Dentistry, Salt Lake City, UT,
United States
S.-K. Kim Pukyong National University, Busan, Korea
J.E. Maté S

anchez de Val Universidad Cat

olica San Antonio (UCAM), Murcia,
Spain
C. Murray European University College, Dubai, UAE
x List of contributors

M. Pe~
narrocha-Diago University of Valencia, Valencia, Spain
V. Perrotti University “G. d’Annunzio”, Chieti, Italy
A. Piattelli University “G. d’Annunzio”, Chieti, Italy
R.L. Reuben Heriot-Watt University, Edinburgh, United Kingdom
J. Ricci New York University College of Dentistry, New York, NY, United States
M.S. Shim Incheon National University, Incheon, Republic of Korea
D. Soto-Pe~
nazola University of Valencia, Valencia, Spain
E.M. Staderini Western Switzerland Universities of Applied Sciences, Geneva,
Switzerland
P.P. Valentini University Tor Vergata, Rome, Italy
K. Vandamme KU Leuven, Leuven, Belgium; U.Z. St. Raphaël, Leuven, Belgium
J. Venkatesan Incheon National University, Incheon, Republic of Korea
I.-S. Yeo Seoul National University, Seoul, Korea
B. Zavan University of Padova, Padova, Italy
Introduction to bone response
to dental implant materials 1
V. Perrotti, F. Iaculli, A. Fontana, A. Piattelli, G. Iezzi
University “G. d’Annunzio”, Chieti, Italy

1.1 Introduction
1.1.1 Bone structure in the aspect of functionality
Bone tissue, originating from mesenchymal tissue, is a type of specialized connective
tissue that functions as a support. It is involved in many processes, which are essential
for the human body. Bone is uniquely designed for its role of providing mechanical
stability to the skeleton, which is needed for load bearing, locomotion, and protection
of internal organs; it presents characteristics such as strength, hardness, and resistance
to pressure, traction, and torsion. Furthermore, the homeostasis of calcium level in
blood is maintained because the mineral calcium, which is stored in the bone, is mobi-
lized from the storage reserve to enter the blood. The diversity of the bone functionality
can be attributed to its complex structure. Indeed, most of the unique properties of the
bone are related to its specific constitution.
Bone is composed of cells and an intercellular matrix rich in organic compounds,
mainly type I collagen fibers embedded in a ground substance consisting of proteogly-
cans, glycoproteins, as well as inorganic minerals. The collagen fibers form bundles or
fibrils, which resist the pulling forces, whereas the minerals provide stiffness, which
resists bending and compression. Bone minerals are mainly in the form of crystals
of calcium phosphateecalcium hydroxyapatite (HA) and when associated with
collagen fibers give the specific hardness to the bone.
Although the bone is populated by a variety of different cells, its functional integrity
is guaranteed by four principal cell types: the osteoclasts (OCLs), bone-destroying
cells; the osteoblasts (OBLs), bone-forming cells; the osteocytes (OCTs), bone-
maintaining cells; and the endothelial cells (ECs), bone-related angiogenic cells. All
of them have defined tasks and are thus essential for the maintenance of a healthy
bone tissue.
OCLs are large, multinucleated cells formed by the self-fusion of macrophages
(Fig. 1.1). They are located on the bone surface in shallow pits called resorption
pits or Howship’s lacunae. The main function of OCLs is resorption of the bone tissue.
The OCLs are able to resorb the strong matrix by secreting acid and collagenase.
Resorption plays a crucial role in the maintenance, repair, and remodeling of bones.
OCLs are formed by the fusion of mononuclear precursors derived from the pluripo-
tential hematopoietic stem cells and share more committed hematopoietic progenitors
with cells of the mononuclear phagocyte system [1].

Bone Response to Dental Implant Materials. http://dx.doi.org/10.1016/B978-0-08-100287-2.00001-X

Copyright © 2017 Elsevier Ltd. All rights reserved.
2 Bone Response to Dental Implant Materials

Figure 1.1 High-power XY view of a multinucleated OCL (asterisks) in peripheral blood

mononuclear cell cultures of the bovine bone. Red indicates positive staining for
F-actineenriched patches and rings with phalloidinetetramethylrhodamine B isothiocyanate
(TRITC) indicating activated OCLs (red arrows). Green indicates positive staining for the
monoclonal antibody 23C6 to detect human integrin alpha V beta 3 complex of the vitronectin
receptor, scale bar 1/4 10 mm.

OBLs are mononucleate cells of mesenchymal origin that are responsible for the
bone formation; they are located mostly on the surface of the bone, as a single layer
of mononuclear cells (Fig. 1.2). Their function is to produce the organic components
of the bone matrix. When active, they show high alkaline phosphatase activity. OBLs
eventually become trapped in the matrix they produce and become OCTs.
OCTs are star-shaped cells that occupy the lacunae in the bone matrix and are the
most common cell types in the bone (Figs. 1.3 and 1.4). They show thin cytoplasmic
processes called filopodia that form a network of small canals called canaliculi. This
network is essential for the exchange of nutrients and waste. OCTs are very long-
living cells, with a half-life of 25 years, and are not capable of division. These cells
have a mechanosensory activity, they have reduced synthetic activity, but are also
able to break down the bone matrix through a mechanism called osteocytic osteolysis
that releases calcium ions for calcium homeostasis and has an important role in
phosphate metabolism. Besides these functions in molecular synthesis and modifica-
tion, OCTs are able to transmit signal over long distances through canaliculi. There
is growing evidence that OCTs are regulatory cells that control the function of
OBLs and OCLs.
Introduction to bone response to dental implant materials 3

Figure 1.2 A rim of OBLs producing osteoid matrix. Toluidine blue and acid fuchsin staining;
original magnification 200.

Figure 1.3 (a) Histological image showing OCTs in the peri-implant bone tissue of samples
retrieved from humans after a loading period of 4 weekse7 months. (b) Images showing how
the count of the number of OCTs was undertaken. OCTs lacunae were highlighted in red.
Toluidine blue and acid fuchsin staining; original magnification 100.

ECs are very flat, they form pavement-like patterns on the inside of the vessels and
are known to function in a variety of important physiological processes. Essentially,
ECs secrete a number of mediators (factors), which may elicit biological responses
by various signal-transduction mechanisms. Such mediators are implicated in regu-
lating the permeability of the endothelium and can promote chemotactic responses,
such as inflammation and blood clotting.
It is well established that bone formation is an angiogenesis-dependent process [2],
and ECs have long been known for their role in the formation of blood vessels that
supply oxygen and nutrients to the developing bone tissue. However, it has been
4 Bone Response to Dental Implant Materials

Figure 1.4 Regenerative potential of collagenated biomaterial grafts. Representative subvolume

of a collagenated biomaterial as retrieved from in vivo test after 12 months and studied by
synchrotron radiationebased, phase-contrast microtomography. Legend: red phase,
regenerated vessels; white phase, newly formed bone and bone under remodeling; green
phase, fully mineralized bone and residual scaffold.
Courtesy Dr. Alessandra Giuliani, Universit
a Politecnica delle Marche, Ancona, Italy.

suggested, more recently, that ECs may play a more direct role in bone development
and formation through their interactions with osteoprogenitor cells [3] and, under
certain conditions, their production of specific bone-inductive factors [4].
At the macroscopic level, the bone is arranged in two architectural forms: dense
compact bone (cortical, around 80% of the total skeleton) and cancellous (trabecular,
around 20% of the total skeleton) bone (Fig. 1.5). Cortical bone is dense and made of
multiple stacked layers with less than 10% porosity.
It is organized in cylindrical shaped elements called osteons, composed of concen-
tric lamellae (Fig. 1.6).

Figure 1.5 Histological image of the dense cortical bone tissue. Toluidine blue and acid fuchsin
staining; original magnification 200.
Introduction to bone response to dental implant materials 5

Figure 1.6 Histological image of osteons consisting of concentric layers, or lamellae, of

compact bone tissue that surround a central canal, the Haversian canal. Toluidine blue and acid
fuchsin staining; original magnification 100.

The space between osteons is occupied by interstitial lamellae, which are remnants
of osteons partially resorbed during bone remodeling. Osteons are cylindrical
structures that are usually several millimeters long and around 0.2 mm in diameter.
The center of an osteon is made of a central canal, called the Haversian canal, that
contains the bone’s nerve and blood supply. On the surface of the osteon, the boundary
is formed by the cement line (Fig. 1.7).

Figure 1.7 Histological image of a secondary osteon, showing the cement line formed as a
result of bone remodeling process. Toluidine blue and acid fuchsin staining; original
magnification 200.
6 Bone Response to Dental Implant Materials

Figure 1.8 Histological image of the trabecular bone with wide marrow spaces. Toluidine blue
and acid fuchsin staining; original magnification 100.

Cortical bone is usually found on the surface of bones. In contrast, cancellous bone
is organized in a porous sponge-like pattern (50e90% porosity) and it consists of a
honeycomb of branching bars, plates, and rods of various sizes called trabeculae
and oriented according to the direction of the physiological load (Fig. 1.8).
It is much softer, weaker, and more flexible than the cortical bone and therefore has
a higher surface area to mass ratio, which makes it suitable for metabolic activity such
as the exchange of calcium ions. It is found in most areas of the bone that is not under
high mechanical stress. Cancellous bone makes up the bulk of the interior of most
bones. The difference in tissue arrangement between the two types of bone provides
increased resistance to torsion and bending; the resistance to torsion and bending by
cortical bone is around 20 times superior compared to that by cancellous bone.
At the microscopic level, cortical and cancellous bone may consist of woven or
lamellar bone. Woven bone is organized in a small number of randomly oriented
collagen fibers and contains a high proportion of OCTs (four times the number of
OCTs per unit of volume compared to lamellar bone; Fig. 1.9).
Lamellar bone is highly organized in concentric sheets filled with many collagen
fibers parallel to other fibers in the same layer and contains a low proportion of
OCTs. After a fracture, woven bone quickly forms and is gradually replaced by
slow-growing lamellar bone through a process known as “bony substitution.”
Bone is a dynamic, highly vascularized tissue with the unique capacity to heal and
remodel without leaving a scar. The dynamics of bone formation involves three
different processes:
• Growth
• Modeling
• Remodeling
During childhood and the early years of adulthood, while the epiphyses are still open,
the skeleton grows in length (growth), the bones expand in diameter and achieve their
external shape (modeling). During bone modeling, OBLs and OCLs work
Introduction to bone response to dental implant materials 7

Figure 1.9 A light micrograph under the polarized light of human bone, where an osteon,
typical of lamellar bone, is evident. Toluidine blue and acid fuchsin staining; original
magnification 100.

independently of each other and on different bone surfaces. The net balance is positive
and it results in bone expansion, with the bone formation exceeding bone resorption.
Bones reach their final external form and high bone density during this period. Both
the growth and the modeling processes are controlled by hormones and mechanical
forces. Following growth, bone volume remains static, with resorption and formation
being in balance. Around the age 20e25 years, peak bone mass is achieved as a result
of these processes. However, in later life resorption exceeds formation, leading to a slow
decline in the bone mass. There is thus an unavoidable loss of the bone mass with age
and a disruption of the trabecular network, which makes fortuitous osteoclastic perfora-
tions possible. Loss of the bone mass with age is unavoidable and is caused by the third
processdbone remodeling. The latter process occurs once growth and modeling of the
skeleton have been completed. It is likely that the major reason for remodeling is to
enable the bones to respond and adapt to mechanical stresses, for example, as a result
of physical exercise and during mechanical loading (e.g. orthodontic tooth movement
or implant loading). Moreover, bone remodeling is designed to maintain a physiologi-
cally and mechanically competent skeleton and to repair areas of microdamage. Wolff’s
law states that bones develop a structure most suited to resist the forces acting upon
them, adapting both the internal architecture and the external conformation to the change
in external loading conditions. This change follows precise mathematical laws. When a
change in loading pattern occurs, stress and strain fields in the bone are modified
accordingly. Bone tissue detects the local change in strain and then adapts accordingly.
The internal architecture is adapted in terms of change in density and disposition of
trabeculae and osteons, the external conformation in terms of shape and dimensions.
When strain is intensified, the new bone is formed. The process is complex and requires
interaction between different cell phenotypes that are regulated by a variety of biochem-
ical and mechanical factors.
8 Bone Response to Dental Implant Materials

Many oral conditions could lead to bone loss, such as infection, trauma, resorption
after tooth extraction or surgical bone resection, and aging. It is imperative to restore
the bone loss, which is the first step in any further prosthetic restoration. Various
surgical solutions have been developed that allow the recovery of the lost bone. These
techniques are combined with the use of biocompatible materials acting as scaffolds in
supporting the bone regeneration.

1.1.2 Bone remodeling

The current concept of bone remodeling is based on the hypothesis that OCL precur-
sors become activated and differentiate into OCLs and this begins the process of bone
resorption. This step is followed by a bone formation phase. The number of sites
entering the bone formation phase, called the activation frequency, together with the
individual rates of the two processes, determines the rate of tissue turnover [5]. The
signal that initiates bone remodeling has not been identified yet. Recently, it has
been shown that mechanical stress can be sensed by OCTs and that these cells secrete
paracrine factors such as insulin-like growth factor I (IGF-I) in response to mechanical
forces [6]. Although IGF may act as a coupling factor in the bone remodeling cycle, the
signal that initiates the cycle remains elusive. The sequence of events in the normal
remodeling cycle is always the same, osteoclastic bone resorption, a reversal phase,
followed by osteoblastic bone formation to repair the defect.
The termination of bone resorption and the initiation of bone formation in the
resorption lacunae occur through a coupling mechanism [7]. The coupling process
ensures that an equivalent amount of bone is laid down following the previous resorp-
tion phase. The detailed nature of the activation and coupling mechanism is still
unknown, although the roles of some growth factors and proteinases such as
transforming growth factor-b1 (TGF-b), IGF-I, IGF-II, and plasminogen activators
have been indicated [8]. Whether the activation of OBLs begins simultaneously
with OCLs’ recruitment or at some later stage during the lacunar development is still
not clear. Bone remodeling is regulated by systemic hormones and by local factors,
which affect cells of both the OCL and OBL lineage and exert their effects on the repli-
cation of undifferentiated cells, the recruitment of cells, and the differentiated function
of cells [9]. The end product of remodeling is the maintenance of a mineralized bone
matrix and the major organic component of this matrix is collagen I (COL-1). The local
factors are synthesized by skeletal cells and include growth factors, cytokines, and
prostaglandins. Growth factors have effects on cells of the same class (autocrine fac-
tors) or on cells of another class within the tissue (paracrine factors).
Growth factors are also present in the circulation and may act as systemic regulators
of skeletal metabolism, but the locally produced factors have more direct and impor-
tant functions in cell growth. Growth factors may play a critical role in the coupling of
bone formation to bone resorption and possibly in the pathophysiology of bone
disorders.
Bone resorption is stimulated or inhibited by signals from other parts of the body,
depending on the demand for calcium. Calcium-sensing membrane receptors in the
parathyroid gland monitor calcium levels in the extracellular fluid. Low levels of
Introduction to bone response to dental implant materials 9

calcium stimulate the release of parathyroid hormone (PTH) from chief cells of the
parathyroid gland. In addition to its effects on the kidney and intestine, PTH also -
increases the number and activity of OCLs to release calcium from the bone and
thus stimulates bone resorption. High levels of calcium in the blood, on the other
hand, leads to decreased PTH release from the parathyroid gland, decreasing the num-
ber and activity of OCLs, resulting in less bone resorption.
OBLs stimulate osteoclastic differentiation of OCL precursors through Wingless-
related integration site 5a (Wnt5a) signaling. The matricellular signaling effected by
TGF-b1 and IGF-1 is integrated with the Sema4D-Plexin B1-mediated OCLeOBL
interaction. Sema4D, whose secretion by OCLs is stimulated by increased OCL
differentiation factor receptor activator of nuclear factor kappa-B ligand (RANKL),
inhibits OBLs’ differentiation. OBLs are induced to migrate to the resorption sites
and differentiate through the secretion of Wnt10b by OCLs at the end of the resorption
phase. OBLs, in turn, inhibit osteoclastogenesis (and therefore bone resorption) via
osteoprotegerin (OPG) and RANKL secretion.
OCTs regulate bone formation through the release of Wnt antagonists, Sclerostin
and Dickkopf-related protein 1, which in turn are inhibited by mechanosignals and
PTH. Wnt signaling in OCTs controls the production of OPG, a decoy receptor for
the key RANKL. In the bone resorption cavity, calcium, TGF-b1, and IGF-1 are
released in response to osteoclastic activity. A number of paracrine signals are
stimulated in OCTs following changes in skeletal loading, including prostaglandin
I2 and prostaglandin E2, nitric oxide, and IGF. Recent studies have raised the
intriguing possibility that the OCT apoptosis may be part of the mechanism whereby
OCLs are targeted to sites of bone resorption as it is elevated in the bone that is being
remodeled. Estrogen suppression, a known stimulant of bone resorption, increases
OCT apoptosis, and changes in bone loading are also associated with OCT apoptosis.
The phenotype of the OCTs appears deficient in some receptors found on the OBL.
However, the OCT is well adapted for its role in bone homeostasis and maintains intra-
cellular signaling to respond to the unique demands of its location.
It is well established that the bone formation is an angiogenesis-dependent process
[2], and ECs have long been known for their role in the formation of blood vessels that
supply oxygen and nutrients to the developing bone tissue. However, it has been sug-
gested, more recently, that ECs may play a more direct role in the bone development
and formation, through their interactions with osteoprogenitor cells [3] and, under
certain conditions, their production of specific bone-inductive factors [4]. ECs secrete
a number of mediators (factors), which may elicit biological responses by various
signal-transduction mechanisms. Such mediators are implicated in regulating the
permeability of the endothelium and can promote chemotactic responses in a variety
of important physiological processes, such as bone formation, remodeling, and heal-
ing. Indeed, it is the capillary that supplies oxygen and nutrients and removes calcium
and waste products of resorption. One of the most important nutrients transported via
the vasculature to the basic multicellular unit is oxygen. In the absence of oxygen,
OBLs cannot produce collagen effectively and their proliferation is reduced. Cellular
responses to changes in oxygen tension are directed through the activity of the
hypoxia-inducible factor (HIF), which is capable of activating the gene transcription
10 Bone Response to Dental Implant Materials

in response to low oxygen levels. OBL-specific knockdown of HIF1a or HIF2a has

demonstrated important roles for HIF in controlling bone formation and vascularity.
Furthermore, low oxygen environments encourage OCL HIF1a stabilization leading
to increased OCL number.

1.1.3 The modern concept of biocompatibility

For over 50 years, biocompatibility consisted of implantable medical devices that
should remain in contact with the tissues of the human body for a long time, without
showing any adverse effect on those tissues from a chemical and biological point of
view.
The first generation of implantable devices was designed and developed during
the 1940s, and over the next few decades it became obvious that the best biological
performance would be achieved with materials that showed the least chemical
reactivity.
The selection criteria for implantable biomaterials included a list of events that had
to be avoided, such as the local or systemic release of some products of corrosion or
degradation, additives or contaminants of the main biomaterial, and their subsequent
biological reaction. So, materials were selected if they were nontoxic, nonimmuno-
genic, nonthrombogenic, noncarcinogenic, and nonirritant.
Three important factors initiated a reevaluation of the biocompatibility concept:
1. The response to specific materials could vary from one application site to another, showing
that the biocompatibility was dependent both on the material characteristics and on its
application;
2. The material should specifically react with the surrounding tissues in a positive way, avoiding
any adverse effect;
3. The material should degrade over time in the body rather than remain indefinitely.
Accordingly, biocompatibility was redefined in 1987 as follows: “Biocompatibility
refers to the ability of a material to perform with an appropriate best response in a
specific situation” [10]. Because this definition appeared to be too general, because spe-
cific mechanisms, such as individual involved processes or innovation of new
biomaterials, were not provided, a modern approach defined biocompatibility as “a com-
plex that depends on the characteristics of a material and on the biological host system.”
Once grafted, the biomaterial should interact with cells of the host tissue, producing
an appropriate response, which would lead to the desired clinical outcome through a
combination of positive effects on critical cells and the avoidance of negative impact
on others. The critical cells could be embryonic stem cells, ECs, or OBLs. The time scale
may be minutes, hours, days, or years and the clinical outcome could be tissue replace-
ment, functional support, tissue regeneration, etc. The biomaterial influences the events
within the biological environment by either mechanical or molecular signaling
processes, or more commonly by both. The biomaterial encounters macromolecules
in the environment and becomes coated by an adsorbed layer typically composed of
proteins, which may be coupled with biomaterial-derived ions or molecules. All subse-
quent interactions will take place between macromolecule-coated biomaterial and
Introduction to bone response to dental implant materials 11

surrounding tissues. Although because a material may affect different biological systems
in different ways, there is not a material with unique biocompatibility characteristics.
Bone substitute materials should have osteoconductive properties, become inte-
grated in bone and replace it, allow ingrowth of blood vessels, and be easy to use as
well as cost-effective. However, the modern concept of biocompatibility implicates
that biomaterials, besides osteoconductivity, should also show osteoinductive and
even osteogenic properties. Osteoconductive materials are composed of a matrix
that acts as a scaffold for the bone deposition. Osteoinductive materials contain mol-
ecules that stimulate differentiation of progenitor cells into OBLs. Some biomaterials
even contain osteogenic cells, OBLs, or OBL precursors, which are capable of forming
bone if placed in the proper environment.
Autologous bone (AB) is the only material characterized by osteogenic properties
with the best results in bone regeneration, although its limited availability and the need
for an additional surgical procedure to harvest the bone are nowadays considered dis-
advantages in its use.
It is extremely important to evaluate the interaction of a biomaterial with the host in
the attempt to establish its biocompatibility and investigate their interactions. A good
biomaterial should stimulate some cells of the receiving site, such as OBLs, OCLs,
cells of innate, and adaptive immunity and platelets. Therefore, the host cells can be
divided into three groups [11]:
1. Target cells
2. Defensive cells
3. Interfering cells
The target cells are the cells at which the therapy is aimed. They could be OBLs in
bone contacting device, stems cells in a tissue engineering bioreactor, or cancer cells in
a polymer-chemotherapeutic agent [12,13]. The defensive cells are cells of innate and
adaptive immunity and platelets. Their existence is based on the need to repel and
remove adverse external agents. The interfering cells are those that are in their natural
habitat and essentially get in the way and interfere with the response, for example,
fibroblasts in the soft connective tissue [14] or OCLs in the bone [15]. The activity
of these cells can lead to hyperplasia or tissue resorption, or other undesirable events.
The involvement of defensive cells in the entire process is inevitable and the critical
question is whether their responses are controlled or uncontrolled. In the latter case, the
cells of the immune system react to the presence of the biomaterial, resulting in the
release of a variety of proinflammatory mediators. The combined cellular and humoral
answer during the inflammatory process can lead to an accelerating and aggressive re-
action that destructs both biomaterial and host tissue [16]. In other cases, the presence
of the irritant biomaterial may lead to giant cell formation and granulation tissue gen-
eration [17]. Interfering cells form part of the normal anatomical structure into which
the biomaterial may be grafted and their influence can have an important effect on the
clinical outcomes. The biomaterial components are usually nonspecific and may
induce uncontrolled response of both defensive and interfering cells, which may
lead to excessive tissue growth, tissue loss, and the loss of function because of the
perturbation of normal homeostasis [18].
12 Bone Response to Dental Implant Materials

Moreover, the biomaterial components can be uptaken by the surrounding cells

through a variety of mechanisms such as phagocytosis, pinocytosis, endocytosis,
or the direct transit through the plasma membrane. Once inside the cell, the component
can directly affect some cellular metabolic pathways or it can be degraded in
endosomes and lysosomes or be altered by the cell enzymes. The products of these
processes also influence the cell metabolism. The generation of reactive oxygen spe-
cies could be induced and, together with alterations in organelle function, can result in
cell damage or interfere with apoptotic and necrotic pathways [19].

1.2 Biomaterials
Several different biomaterials have been used in bone regeneration procedures and all
of them seem to be able to favor the formation of a significant amount of vital bone.
A biomaterial should act as a scaffold for the formation of bone, possesses pore
volume, pore interconnectivity, and pores size adequate to allow the invasion of oste-
ogenic cells and blood vessels, and have mechanical features similar to the tissues to be
regenerated. Biomaterials should, moreover, present a biologic stability, help in the
volume maintenance, and allow for bone remodeling. Macro- and microporosity
and the interconnecting porous structure of the grafted biomaterial play a relevant
role in supporting the penetration, proliferation, and differentiation of OBLs and the
ingrowth of newly formed blood vessels into the biomaterial particles.
Some researchers believe that a biomaterial should be completely resorbed and
replaced by newly formed bone.

1.2.1 Autologous bone

AB is the golden standard of the grafting material due to the presence of vital OBL and
growth factors. It has osteogenic, osteoinductive, and osteoconductive capabilities.
Histology shows that it is a highly osteoconductive material, and most of the particles
are partially and/or completely surrounded by newly formed bone, in tight contact with
the particles. A complete absence of inflammatory cells, multinucleated giant cells, or
foreign body reaction cells should be noted. However, its main disadvantage is related
to its quantity obtained from intraoral sources, and often an additional surgical proce-
dure is required, with a higher morbidity. Furthermore, AB can present a rapid and
unpredictable resorption [20].

1.2.2 Porous phycogenic hydroxyapatite

Porous phycogenic hydroxyapatite (PHA) derived from calcifying maritime algae
(Coralline officialis) is a biologic HA, prepared by the hydrothermal conversion of
the calcium carbonate in the presence of ammonium phosphate at about 700 C.
This process helps in preserving the porous structure of the biomaterial. Its composi-
tion is pure inorganic calcium phosphate. The pores have a mean diameter of 5e10 mm
Introduction to bone response to dental implant materials 13

with a periodical septation with a mean length of 50e100 mm and interconnected by

means of small perforations with a mean diameter of 1e3 mm. Every pore is lined by
fluorhydroxyapatite crystallites, with a size of 25e35 nm [11]. The particles are inter-
connected by microperforations, having a mean diameter of 1 mm. Its elevated micro-
porosity should be helpful in the ingrowth of osteogenic cells and blood vessels.
PHA is a biocompatible, osteoconductive, and resorbable biomaterial. Most
of the biomaterial particles appeared to be surrounded by newly formed bone,
and in a few fields some particles seemed to be partially resorbed and substituted
by newly formed bone. No inflammatory cell infiltrate or foreign body reaction
cells were present; the bone was always in tight contact with the biomaterial parti-
cles with no intervening gaps (Figs. 1.10 and 1.11). Bone was present inside many
biomaterial particles [21,22].

1.2.3 Collagenized porcine biomaterial

Collagenized porcine biomaterial is composed of carbonated nanocrystalline HA,
containing organic material.
Most of the grafted biomaterial particles were surrounded by the newly formed
bone with large OCT lacunae, always in tight contact with the particles, and no
gaps were observed at the boneebiomaterial interface. No inflammatory cells and
multinucleated giant cells were present. Some of the grafted particles were bridged
and cemented by the newly formed bone. Many bone trabeculae were undergoing
remodeling. Porcine bone is a highly osteoconductive biomaterial. It undergoes resorp-
tion, with the presence of active resorption signs (Fig. 1.12). OBLs and newly formed
bone were commonly found on the surface of the biomaterial particles [23e25].

Figure 1.10 Histological image of a sample retrieved 6 months after a sinus lift in a human
subject. Newly formed bone with remodeling areas and residual porous PHA material can be
observed. Toluidine blue and acid fuchsin staining; original magnification 40.
14 Bone Response to Dental Implant Materials

Figure 1.11 High-power histological image of porous PHA particles partially surrounded by the
newly formed bone. Toluidine blue and acid fuchsin staining; original magnification 100.

Figure 1.12 Histological image of a collagenized porcine material used to regenerate a

postextraction socket in humans. The sample was retrieved after a 3-month healing time. The
biomaterial particle is surrounded by the newly formed bone, which can be seen also in the
inner part of the granule. The material’s margin appears indented. Toluidine blue and acid
fuchsin staining; original magnification 100.

1.2.4 Anorganic bovine bone

Anorganic bovine bone (ABB) is a deproteinized bovine bone with a 75e80% degree
of porosity and a size of the crystals of about 10 nm. It presents large pores and a high
connectivity. ABB is one of the most used biomaterials and it has shown good
Introduction to bone response to dental implant materials 15

osteoconductive properties. No inflammatory cell infiltrate, foreign body response, and

other adverse effects are present. A high quantity of new bone formation has been
reported with the use of ABB. Usually, ABB particles seem to be almost completely
surrounded by the newly formed bone. No gaps or connective, fibrous tissue were
observed at the boneebiomaterial interface. Some particles seemed to be bridged by
the newly formed bone. Due to its low resorption rate, ABB may significantly
contribute in the prevention of volume tissue loss in grafted sites opposing, for
example, the sinus pressure due to repneumatization. The ABB particles and the newly
formed bone produce a dense hard tissue supportive, also over the long term, of loaded
implants (Fig. 1.13). This biomaterial has, thus, a long-term, three-dimensional stabil-
ity [26,27].

1.2.5 Biphasic calcium phosphate

Biphasic calcium phosphate (BCP) is composed of a combination of HA and trical-
cium phosphate (TCP) and used in bone regeneration procedures. It has different ratios
of HA/TCP, giving rise to balanced phases of activity, a more stable phase of HA, and
a more soluble phase of TCP. The resorption rate of the material is dependent on the
HA/TCP ratio (a higher TCP means a higher solubility); this material gradually dis-
solves in the body, determining the new bone formation by the release of calcium
and phosphate ions. BCPs are highly biocompatible, and they do not provoke a foreign
body or a toxic response. Most of the grafted BCP particles were partially surrounded
by the newly formed bone with no gaps (Fig. 1.14). Some particles were bridged by the
newly formed bone. Resorption was observed at the surface of some particles
[28,29,30].

Figure 1.13 Histological image of an ABB particle integrated into the bone tissue and bridging
the newly formed bone trabeculae. Toluidine blue and acid fuchsin staining; original
magnification 100.
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