Title
Author(s)
Citation
Issued Date
URL
Rights
Bioactive glasses in cranio-maxillofacial and oral surgery
Vijayakumar, Charanya.
Vijayakumar, C.. (2012). Bioactive glasses in cranio-maxillofacial
and oral surgery. (Thesis). University of Hong Kong, Pokfulam,
Hong Kong SAR. Retrieved from
http://dx.doi.org/10.5353/th_b4854211.
2012
http://hdl.handle.net/10722/180084
The author retains all proprietary rights, (such as patent rights)
and the right to use in future works.
BIOACTIVE GLASSES IN
CRANIO-MAXILLOFACIAL AND ORAL SURGERY
A Thesis
submitted to
The University of Hong Kong
in partial fulfillment for the degree of
Master of Dental Surgery
in
Oral & Maxillofacial Surgery
by
Charanya Vijayakumar
The University of Hong Kong
August 2012
Supervisor
Professor Roger Arthur Zwahlen
MD, DMD
&
Co-Supervisor
Dr Jukka Pekka Matinlinna
BSc, MSc, Ph.D
i
BIOACTIVE GLASSES IN
CRANIO-MAXILLOFACIAL AND ORAL SURGERY
Submitted by
Dr. Charanya Vijayakumar
For the degree of Master of Dental Surgery
at
The University of Hong Kong
in
August 2012
ii
Declaration
I hereby declare that this thesis is an outcome of my original work and has not
been included in whole or in part in any other thesis, dissertation or report
submitted to The University of Hong Kong or to any other institution for a degree,
diploma or any other qualification except where due acknowledgement is made.
Charanya Vijayakumar
iii
Acknowledgements
I would like to take this opportunity to express my deepest gratitude and
appreciation to my supervisor Prof. Roger Arthur Zwahlen for his constant
support and encouragement. His valuable advice and guidance during my entire
course has made me present my focused and devoted work with ease. His
energy and dynamics have always influenced me in productive performance. His
patience and persistent help is much appreciated without which this work would
not have turned out the way it did. I thank him for being my mentor and source of
advice always.
I would also like to extend my heartfelt appreciation and gratitude to my cosupervisor Dr. Jukka Pekka Matinlinna for sharing his knowledge and expertise.
His cheerful attitude, motivation and valuable ideas have made every discussion
at his office very useful and lively. I thank him for accepting this collaboration and
extending his support for this venture.
I would like to extend my special thanks to Prof. Nabil Samman and Prof. Lim
Kwong Cheung for sharing their knowledge and extending their full support and
understanding throughout my three years of study here in Hong Kong and also
the other academic staffs Dr. John Lo, Dr. Alfred Lau, Dr. Winnie Choi and Dr.
Mike Leung for sharing their knowledge and being a great source of learning.
iv
I would like to thank the nurses, DSAs and all the supporting staff of Prince
Philip Dental Hospital and Queen Mary Hospital for their ever helping and warm
attitude which made me feel at home and made these three years a wonderful
and unforgettable period. Appreciations to my batch mates, seniors and juniors
for their help, support and good times in the post graduate room. I had learnt a
great deal from all of them.
My special mention of gratitude to the library staff Ms. Louise Liu and statistician
Mr. Shadow Yeung for their help and support in completing this thesis.
I would like to thank my family for their love, understanding, support and
encouragement to pursue this degree and come out with flying colors. Last but
not the least I would like to thank and dedicate this effort to the Almighty for his
divine blessings to complete my academic endeavors without hassles.
v
Table of Contents
Page
PREFACE
2
PART I : An Overview of Bioactive Glasses
PART II: Bioactive Glasses in Cranio-Maxillofacial and Oral Surgery
5 - 38
39 - 89
– Evidence Based Review
ANNEXES
Figures and Tables
89 - 93
List of Abbreviations
94 - 97
Definitions and Synonyms
98
REFERENCES
99 - 130
1
Preface
Different synthetic bone grafts and novel alloplastic materials represent versatile
options in the field of cranio-maxillofacial and oral bone substitution and/or
augmentation. Nevertheless, autologous bone grafts remain the gold standard for
bone replacement in congenital, developmental and acquired bone defects.1
Autologous bone grafts, however, have inherent short comings such as donor
site morbidity with its concomitant complications as well as their limited volume
availability.2 Although autologous bone grafts have good clinical outcomes, their
long term results are unpredictable and sometimes disappointing.3
As only two randomized control trials could be found, an evidence based review
elucidating the clinical applications of bioactive glass within the craniomaxillofacial and oral area has been performed. This thesis does not engage to
be complete; nonetheless, in the first part a comprehensive survey about the
synthetic bone graft material of Bioglass® related to its components, structure,
biocompatibility and biomechanical properties are given. In the second part, a
summary of hitherto clinical applications of this material highlights its
biocompatibility and its clinical outcomes. At the end, areas of future research
directions are highlighted being important to gain more information regarding the
current knowledge and clinical application of bioactive glass.
2
Part I: An Overview of Bioactive Glasses
Page
1
Definition and Introduction
6-8
2
Background
9 - 10
3
Bioactivity and Classification
4
Tissue Bonding, Toxicity and Biocompatibility
5
Influence and Significance of Essential Components
13 - 24
6
Mechanism of Bioactive Bonding to Tissues
24 - 28
7
Factors Affecting Implant - Tissue Interface
29
8
Composition - Reactivity Boundary
29
9
Properties of the Material that Affect Bone Healing
10
Tissue Responses to Different Materials
31
11
Composition and Commercially Available Products
31
12
Maiden Marketing
31 - 32
13
Clinical Applications
32 - 33
14
Discussion
33 - 38
11 - 12
3
12
29 - 30
Part II: Bioactive Glasses in Cranio-Maxillofacial and Oral Surgery
Page
– Evidence Based Review
1
Abstract
40 - 41
2
Introduction
42 - 45
3
Materials and Methods
45 - 47
4
Results
48 - 66
5
Discussion
66 - 88
6
Conclusion
88 - 89
4
Part I
An Overview of Bioactive Glasses
5
1 Definition and Introduction
A bioactive material elicits a specific biological response at the interface of the
material and the surrounding tissues which results in formation of a biologically
active bond of hydroxyapatite (HA) layer between the tissue and the material.4-6
The particular level of bioactivity can be related to the time which is needed for
more than 50% of the interface to bond to bone (t0.5bb).
Bioactivity Index (IB) = 100/ t0.5bb
Bioactive glasses, including Bioglass® belong to the broad range of inorganic/
non-metallic biomaterial group of surface reactive glasses. Biocompatibility is the
ability of a material to respond to a specific use. It refers to the inherent capability
of that particular material to accomplish its potential function with respect to a
therapeutic treatment without eliciting any undesirable local or systemic effects in
the recipient or beneficiary of that therapy. The effect of treatment should
generate the most appropriate and beneficial cellular or tissue response in a
specific situation by optimizing the clinically relevant performance of that
therapy.7,8 The desired function of physiochemical and biological interactions
between host tissue and the implant surface determine the host’s response. 9 The
biocompatibility of bioactive glasses has led to extensive clinical investigations
related to repair and/ or replacement of bone deficiency.
Bioactive ceramics and glass-ceramics have unique features; one aspect that
makes bioactive glasses different from bioactive ceramics and glass-ceramics is
the feasibility of varying its chemical properties and rate of bonding to tissue.
Glasses can be manufactured with selective properties pertaining to a specific
6
clinical application. This is also possible with some glass-ceramics, but their
heterogeneous macrostructure restricts their versatility.10 For instance, bioceramic scaffolds tend to possess bioactivity, high porosity and sufficient
mechanical properties; however, attempts to improve the mechanical properties
of the widely used, so-called 45S5 Bioglass® turn the bioactive glass itself into a
glass-ceramic, with nontrivial effects on the resulting scaffold bioactivity.11 Glassceramics vary in their crystallization structure from glasses and it is important to
note that not all glasses can be crystallized to produce a glass-ceramic. Some
glasses are too stable and difficult to crystallize, while others are readily
crystallized in an uncontrolled manner leading to an undesirable microstructure.
Hence, the structure of parent glass is critical to produce an acceptable glassceramic. Temperature variations during crystallization affect the composition of
glass and glass-ceramics. It is also worthy to note that the composition of
residual glass in glass-ceramic structure is different from the parent glass, which
implies that each variation in glass-ceramic has its own characteristic internal
structure as consequences of variation in several parameters during its
manufacture. The compositions of most bioactive glass-ceramics are those of
bioactive glasses, but usually with phosphorus pentoxide (P2O5) slightly higher
and sodium oxide (Na2O) less. Based on the composition of parent glass their
crystalline phase apatite could be hydroxyapatite (HA), hydroxy carbonate apatite
(HCA) or fluoroapatite (FA) to synthetically simulate HA of bone. The Young’s
Modulus of silicate based bioactive glasses are 3-4 times greater than that of
cortical bone making them undesirable candidates since the load will be
transferred from the adjacent bone to the stiffer glass implants making them poor
in strength and toughness. The compressive strength is higher in calcium
7
phosphate glasses compared to silicate glasses but the phosphate glasses
showed remarkably high toughness values. The mechanical properties of cast
glass-ceramics are considered better than their parent glasses especially for the
silicate-based materials and their powder-based glass-ceramics were found to
possess superior mechanical properties. Rawlings12 in his paper showed similar
interfacial shear strengths in both bioactive glasses and glass-ceramics; yet their
brittle nature was of concern. Metal reinforcements with stainless steel, titanium
and aluminum have also been tested on glasses to overcome their shortcomings
of strength.12 Osseointegration was first described by Brånemark and coworkers13 and first described in a paper by Albrektsson et al.,14 as the direct
structural and functional union between bone and implant surface. Implant
materials are classified as biotolerated, bioinert or bioactive based on their
interaction with living tissue15 and gauged based on an arbitrary scale of reaction
numbers, with anything more than 5 considered to be bioactive in glasses.12
Bioactive glass-ceramics has substantially greater mechanical properties than
bioactive glasses and are considered suitable for vertebral replacements due to
their large compressive strength. Thompson and Hench in 199816 designed vital
criteria for successful bioactive implants as follows:
i)
Elastic modulus matching to bone,
ii)
Increased toughness,
iii)
Increased fatigue resistance,
iv)
Increased strength and
v)
Maintaining Class A bioactivity.
The evolution of bioactive glasses, bioactive glass-ceramics and their
composites were supposedly aimed to address the above mentioned criteria.
8
2 Background
During his engineering internship in the years 1957-1958, Hench encountered
an interesting experience with glasses while working in the ceramic engineering
laboratory to make formulation of glasses, glazes, enamel and whitewares. 17
Later in his research, he worked with vanadium phosphate (V2O5.P2O5) and
discovered high electronic conductivity resisting radiation damage in these
semiconducting glass-ceramics. As creative thinking begins in a nonconforming
mind that facilitates the ability to realize innovations, Hench conceived the
eventual possibility of creating a material to substitute human limbs in war victims
without being rejected by the human body under unexpected circumstances; thus
beginning the quest for biocompatible and bioactive glass materials.17
The research team around Hench discovered a material later known as
Bioglass®.17 From 1967-1969 they hypothesized that the human body rejects
metallic and synthetic polymeric materials by creating a scar tissue barrier.
According to them, materials that were able to form synthetic HA layers should
not be rejected from bone which contained hydrated calcium phosphate
component.
They first worked with the glass composition 45S5, containing 45% silicon
dioxide (SiO2); 24.5% sodium oxide (Na2O); 24.5% calcium oxide (CaO) and 6%
phosphorus pentoxide (P2O5). This mixture was selected to provide a large
amount of CaO with some P2O5 in a sodium oxide - silicon dioxide (a.k.a., silica)
(Na2O.SiO2) matrix, a composition which is very close to a ternary eutectic,
facilitating its melting. The melted glass was cast into small rectangular implants,
inserted into rat femurs and tested for HA bond with bone in the absence of
implant rejection. After 6 weeks of testing the femoral implant model in rat
9
femurs, none of these glass-ceramic implants was rejected. All became
integrated to bone, not changing their position and proved to be resistant to
various forces; whereas the metallic and polymeric controls easily slid out due to
their inability to form such a bond.17
This animal experiment represented the basis for the first Bioglass® paper being
published in 1971 in the Journal of Biomedical Materials Research 18 and stated
that interfacial HA crystals formed as a result of implant - bone interaction were
observed on the bonded implant - bone interface and was tested by transmission
electron micrographs. These HA crystals adhered to layers of collagen fibrils
produced at the interface by osteoblasts from the host and the chemical bonding
of the synthetic HA layer to collagen created the strongly bonded interface.18-21
This offered positive conclusions about Bioglass® being a biocompatible and
stable bioactive implant material which led to a series of testing in the next ten
years.
“Adhesion to Bone” by Hench and Clark22 explained the physical, chemical and
biological nature, reaction mechanism, nature of bond, strength of bond and if the
bond is influenced by the composition of the implant.
Questions were also
answered on the functional load capacity of Bioglass® and its response to
biological tissues, and were published in 1982.
Subsequent experiments evaluated the interfacial shear strength in rats and
monkeys that were conducted on eight different biomechanical models and
revealed that the strength of the interfacial bond between Bioglass® and cortical
bone was equal to or sometimes even greater than the strength of the host
bone.15,23,24 Weinstein et al.,25 described the biomechanics of the bonded
interface in their article.
10
3 Bioactivity and Classification
Generally, the bioactivity of an artificial material in bone needs to be well
orchestrated to lead to harmonious bone regeneration.4,26,27 The reactivity in bone
must neither be too rapid nor too slow. Large differences in material dissolution
and bone proliferation - differentiation disrupts the synchronized bone
regeneration process and there will be rapid loss of the material causing unstable
or weak bone - bioactive implant interface.28-33 This phenomenon resulted in a
need for classification of bioactivity for various materials according to their
mechanism of action in host environment.28,34-37
Class A bioactivity leads to osteoconduction, osteoproduction and more recently
proven osteoinduction.38 The surface reactions involve ionic dissolution of critical
concentrations of soluble silicon, calcium, phosphorous and sodium ions resulting
in intracellular and extracellular responses at the interface of the glass and its
physiological environment.39 Bioactive glasses are exhibiting an IB value of >8
and hence, are called Class A bioactive materials. They can bond to both bone
and soft tissue, and can induce and stimulate bone growth. The function of Class
A bioactive materials has been attributed to their ability to form a layer of HCA on
the interfacial surface within a few hours.40 Powder-form bioactive glasses are
usually melt-derived and are available in the commercial market for clinical use in
bone repair. During their resorption, the glasses release ionic dissolution
products that have been detected to up-regulate seven families of genes in
osteoblasts.41 Therefore, bioactive glasses are not only bioactive as their name
suggests but also osteoproductive, osteoconductive, osteoinductive 38 and
biodegradable, being replaced by their surrounding tissues as they dissolve.
11
Glasses with class B bioactivity only show osteoconduction; due to slower
surface reactions and minimal ionic release, bone migration occurs along the
interface where also only extracellular responses of complex ionic exchange take
place.39 The whole sequential process may take one to several days to happen.
The glasses of this class essentially bond only to bone. With an IB value >0 but
<8, soft tissue bonding is lacking.40 Classical examples of this group are glassceramics like tricalcium phosphate ceramics and synthetic HA.
Bioactive glasses and glass-ceramics share their characteristic feature of timedependant kinetic modification of the surface reactions upon implantation.42 The
surface forms a biologically active HCA layer that provides the bonding interface
for the implant with tissues.43 Unlike bioactive glasses, glass-ceramics are not as
effectively bioactive and biodegradable; therefore, glass-ceramics are less
suitable as bone scaffolds or bone substitutes compared with bioactive glasses.
4 Tissue Bonding, Toxicity and Biocompatibility
Wilson et al.,44 made the very interesting discovery in 1981 that connective
tissues could also form a bond to 45S5 Bioglass®, if the interface is kept
immobile. Rapidly reactive glasses bond with soft tissue whereas glass
composition exceeding 52 wt. % of SiO2 will bond to bone but not to soft
tissues.45 This particular mechanism of its reactivity to tissues was the basis for
its clinical use in ossicular replacement and also for alveolar ridge maintenance.
The toxicology tests of bioactive glasses have shown that these materials are
acceptable for clinical use.44,46
12
5 Influence and Significance of Essential Components
There are three pivotal compositional features that distinguish highly reactive
bioactive glasses from traditional sodium oxide - calcium oxide - silicon dioxide
(Na2O.CaO.SiO2) glass. Melt-derived bioactive glasses become highly reactive
when exposed to an aqueous medium and dependent on the following:
(i)
Less than 60 mol. % of SiO2,
(ii)
High CaO/ P2O5, and
(iii)
High Na2O and CaO content.
Composition of SiO2 is crucial for bioactivity and bone bonding mechanisms.
Silicon dioxide in the glass between 52-60 wt. % exhibited slower rates of
bonding, whereas compositions greater than 60 wt. % of SiO2 did not bond and
became bioinert. Increasing the surface area extended the bone bonding
compositions to higher percentages of SiO2. Addition of cations, such as Al3+, Ti4+
or Ta5+ to the glass shrank the bone bonding boundary and must be kept in mind
as they alter the bioactivity of the implant material.47-50
Glasses with substantially lower molar ratio of calcium to phosphorus in the form
of calcium oxide and phosphorus pentoxide did not bond to bone. However,
neither substitutions of 5-15 wt. % of boron trioxide (B2O3) for SiO2 or 12.5 wt. %
of calcium fluoride (CaF2) for CaO in the 45S5 Bioglass® formula, nor crystallizing
various bioactive glass compositions to form glass-ceramics resulted in notable
ability to create a bone bond.20 Versatility of bioactive glass compositions
exhibited a stable bioactive glass surface using three different compositions to
chemical etching and noted characteristic surface reactions without any
interference in its formation by soaking them together with its control in simulated
body fluid (SBF), which is an acellular, inorganic ion concentration designed
13
similar to those of human extracellular fluid and Tris solution, a kind of buffer
solution used for various biochemical experiments.51
Ebisawa et al.,52 studied the compositional dependence of the bioactivity of
phosphorus pentoxide and sodium oxide free calcium oxide - silica (CaO.SiO2)
glasses in SBF. The same authors observed when adding a third component that
phosphorus pentoxide free calcium oxide - silica glass bonded to living bone.
Further on, an increased bioactivity with the addition of a third component of
sodium oxide or phosphorus pentoxide; and decreased bioactivity with the
addition of magnesium oxide (MgO), boron trioxide, calcium fluoride and ferric
oxide (Fe2O3) were revealed. In a similar experiment, it was tried to study the
bioactivity of calcium oxide and silica by adding third components such as sodium
oxide, magnesium oxide, boron trioxide, phosphorus pentoxide and calcium
fluoride after the materials were soaked in SBF for 8-25 weeks. Implantation was
observed after eight weeks inferring that glasses containing B2O3, P2O5 and Fshowed good compatibility, hence bonding tightly with bone; whereas ferric oxide
containing glasses showed no compatibility with bone even after 25 weeks.53
Calcium oxide - silica glasses without phosphate formed an apatite layer on their
surface in SBF when soaked for 2-30 days54 and were bioactive both in vitro and
in vivo.55 Phosphorus pentoxide free sodium oxide - silica glasses formed an
apatite layer on their surface when exposed to aqueous solution containing both
calcium and phosphate ions.56 However, it was demonstrated later that glasses
containing primarily silica with only 10 mol. % of calcium oxide and phosphorus
pentoxide in the absence of sodium oxide formed apatite layers in a Tris buffer
solution.57 Walker58 then in 1977, already demonstrated that even nearly pure
silica formed a bone bond when presenting a surface area >400 m2/ g. Although
14
it has been said that synthetic HA implants can still bond to bone in the absence
of silica or alkali ions by forming a new epitaxial apatite phase at the interface,
unfortunately so far, there is no substantial evidence to prove the presence of an
interfacial apatite layer which could have been nucleated on the surface by
hydroxylation and/ or dissolution of soluble silica.27 Conclusively, a certain
inference about the influence of silicon dioxide is difficult to deduce.
If yttrium trioxide (a.k.a., Yttria) (Y2O3) was added in high amounts to substitute
calcium oxide, the bioactivity of calcium oxide - silica (2.5CaO.2SiO2) glasses
decreased because of the limited capacity to form a calcium phosphate layer. 59
More yttria can be substituted without inhibiting the reaction with SBF.10 However
as suggested by Kokubo et al.,54 there must be a critical analysis of the results
before concrete conclusions, as careful selection of simulated body fluid for in
vitro experiments is essential to simulate the results in vivo.
Filqueiras et al.,60 reported that the substitution of calcium oxide by magnesium
oxide had little effect on bone bonding, while additions of 1-1.5 wt. % of aluminum
trioxide (AI2O3) prevented it. Lockyer et al.,61 later in 1995, studied the properties
of some glasses when calcium oxide was substituted by sodium oxide. The
preferential association of sodium and calcium ions caused the changes in the
chemical shifts of these two species. This phenomenon of preferential chemical
reaction suggested that appropriate division of these components determined its
bioactivity at the interface between the glass and the physiological environment
by controlling the dissolution, hydrolysis and condensation of these ions.
The first commercially available glasses that incorporated magnesium oxide
were Ceravital® glasses and the resulting glass-ceramic materials obtained from
its parent glass. Ceravital® glasses contained a base composition, 40-50 wt. % of
15
SiO2, 10-15 wt. % of P2O5, 5-10 wt. % of Na2O, 0.5-3.0 wt. % of K2O and 2.5-5
wt. % of MgO. Glasses and glass-ceramics such as KOMAGE Gellner Ceramics
(KG Cera) with 2.9 wt. % of MgO and Mina with 5 wt. % of MgO were derived
from them. Ohtsuki et al.,62 detected an intimate contact between living tissues
and these materials.
Already in 1990, Vogel and Holand63 developed the so-called Bioverit® family of
glass-ceramic materials in which MgO content ranging between 6 and 28 mol. %.
These glass-ceramics had apatite, mica and/ or cordierite phases in their
structure. The authors reported a direct intergrowth between materials and living
tissues. The role of magnesium oxide in glasses and glass-ceramics of the
system CaO.P2O5.SiO2.MgO-(AI2O3) was investigated in a pseudo-extracellular
fluid. It was found that MgO contents in glass-ceramics greater than 8 wt. %
decreased the ability to form the apatite layer.64
Kokubo et al.,65 worked with glasses of silica - calcium oxide - phosphorus
pentoxide - magnesium oxide (SiO2.CaO.P2O5.MgO) composition and developed
the apatite-wollastonite containing glass-ceramic (A-W.GC) with 4.6 wt. % of
magnesium, 44.7 wt. % of calcium oxide, 34.0 wt. % of silica, 16.2 wt. % of
phosphorus pentoxide and 0.5 wt. % of calcium fluoride. Apatite-wollastonite
containing glass-ceramic (A-W.GC) was obtained by crystallization of a glass
powder compact. They also developed the apatite glass-ceramic (A.GC) and
apatite-wollastonite calcium phosphate glass-ceramic (A-W-CP.GC), the former
rich in apatite and the latter in apatite, wollastonite and tricalcium phosphate. In
simulated body fluid, both materials produced a HCA layer similar to the one
developed on Bioglass® surface with their similarities of compositional and
structural characteristics intact. Ceramic leaching with dissolution of calcium and
16
silicon increased the local fluid super saturation of apatite; followed by the
dissolution of silicate ions by nucleation on the material which subsequently
explained the bioactivity mechanism of these glasses.
Ohtsuki et al.,55 worked with CaO.SiO2.P2O5 glasses and showed that the
degree of super saturation was the best in calcium oxide - silica glass. There was
higher rate of apatite nucleation on the surfaces of these glasses compared to
the rest and was attributed to the lower interface energy between the apatite and
the glass surfaces. Silica hydrogel was seen on the reaction surfaces prior to the
formation of apatite layer in calcium oxide - silica based glasses, proving that the
hydrated silica layer are favorable sites for the apatite nucleation. Non-bioactive
alumina-containing apatite-wollastonite glass-ceramic A-W-(AI) developed an
apatite-rich layer when immersed in synthetic fluid with concurrently added
calcium and silicate ions, suggesting that soluble silicate ions played an important
role in silica layer formation. The apatite phase present in glass-ceramic did not
play an important role in forming the chemical bond to bone as proven by various
surface chemical studies; it was in fact the calcium - phosphorus rich layer on the
surface of glass-ceramic materials that played an essential role in the body
environment by forming the chemical bond of glass-ceramic to bone, thereby
displaying its bioactivity. It was further concluded that various kinds of bioactive
materials with different function can be designed using glasses and glassceramics owing to its versatility.66
In molecular orbital models, West and Hench67 proposed that only a specific
structural unit of silanol groups, Si-OH, (trigonal siloxane rings) is effective for
apatite
nucleation.
Roman
et
al.,68
studied
bioactivity
of
CaO.SiO2.P2O5.MgO.CaF2 of the so-called G13 glass, inducing bioactivity in a
17
non-bioactive ceramic (GC13) after chemical treatment with 1ml hydrochloric acid
(HCI) for different time periods in vitro studies. Results showed that the etching
time influenced kinetics of apatite-like layer formation in SBF. Further, the
microstructural and morphological fluctuations associated with the presence of
HA crystal favored the bioactive behavior of GC13 ceramics etched for one
minute
in
vitro.
A
new
composition
of
bioactive
glass-ceramic
CaO.MgO.SiO2.P2O5 was developed by Liu et al., in 1994.69 The authors
deduced superior strength and fracture toughness in this glass-ceramic system
compared to the apatite-wollastonite material. In vitro studies demonstrated
formation of an apatite layer on a glass-ceramic surface using scanning electron
microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) studies.
These investigations displayed that glass-ceramic had flexural strength, fracture
toughness, and also exhibited a high bioactivity with load bearing medical
applications.10
Glass and glass-ceramic of MgO.CaO.P2O5.SiO2 glass composition were
prepared and tested by Oliveira et al., in 1995.70 The calcium - phosphorus rich
layer was identified as hydroxyapatite on both glass and glass-ceramic samples
after immersion in SBF for different time periods. While the precipitated films on
glass samples were weakly bonded, the one of glass-ceramics were strongly
adhered. These microstructural characteristics were observed in SEM studies.
The authors came to the conclusion that, though the glass-ceramic had higher
chemical and mechanical stability; the glasses were expected to be capable of
bonding to bone with good bioactivity.
Lin et al.,71 studied the structural and elastic properties of two bioactive glasses,
sodium - calcium - silicon oxide (Na2CaSi2O6), of the so-called 45S5.2
18
composition and sodium - calcium - silicon oxide (Na2CaSi3O8), of the so-called
55S4.1 composition by employing Raman and Brillouin scattering techniques
which are powerful laser-based methods to perform nondestructive evaluation of
these materials in their solid state. It was observed that the annealed 45S5.2
glass showed higher elasticity than the 55S4.1 glass due to more compositional
modifiers in 45S5.2 glass. Modifications by adjusting the silicon + phosphorus
(Si4++P5+) / sodium + calcium (Na++Ca2+) composition produced the elasticity of
the 45S5.2 glass and was concluded to be a better bone substitute than its
parent glass. Similarly, Serra et al.,72 studied bonding configurations of bioactive
silica-based glasses and identified the silicon-oxygen groups by combining two
spectroscopic techniques; x-ray photoelectron spectroscopy (XPS) and infrared
spectroscopy (IR). The breakage of silicon – oxygen – silicon (Si–O–Si) bonds
and the formation of silicon – oxygen – non-bridging oxygen groups play an
important role on the biological response at the interface of the bioactive
materials when exposed to body fluids. The experimenters concluded that critical
analysis of the bonding configuration in different bioactive glasses is a prime step
for future innovations in glasses and its biomedical application.
Peitl et al.,73 showed in their in vitro test on 45S5 Bioglass® with simulated body
fluid (SBF)-K9 that the onset time for HCA layer formation decreased with
increased crystallinity. They concluded that crystallization did not significantly
affect the kinetic reactions in wt. % of 1.5 Na2O and 1.5 CaO = 3 SiO2 containing
0, 2, 4, and 6 wt. % of P2O5 glasses. Crystallinity up to 100% was noted with no
loss in bioactivity, which was contrary to the results produced by other
investigators who worked with glasses of related compositions. This system of
glasses showed high bioactivity even in the absence of phosphorus compared to
19
other commercial bioactive glass-ceramics. They further revealed the in vitro
bioactivity of partially crystallized 45S5 Bioglass® as a function of time through in
situ observation using atomic force microscopy (AFM). The reaction rate
observed in 45S5 glass-ceramic was found to be seven times faster than that
reported for apatite-wollastonite glass-ceramics with respect to the formation of
crystalline HCA. Thermal treatments carried out to obtain a material being less
resorbable, able to retain its bioactivity and stiffer than standard Bioglass®,
resulted in crystallized Bioglass®.
The formation and growth of calcium
phosphate layer on partially crystallized 45S5 Bioglass ® was 15-30 times larger
than those formed on hydroxyapatite.
But this difference was noted only within
the first 15 minutes and was found to be similar to that of crystallized
hydroxyapatite C planes after this initial phase.74 This suggested that crystallized
Bioglass® could be a more suitable filler material compared to crystallized
hydroxyapatite owing to its hyperactive primary stability.
More in vitro tests were performed to study the surface reactions of micro
roughened bioactive glasses by employing a novel chemical etching method.
Itälä et al.,51 prepared porous bioactive glasses and immersed them in SBF for
several hours to analyze them using scanning electron microscope and energy
dispersive x-ray analysis (EDX) studies. It was inferred that micro roughening
significantly accelerated the early formation of surface reaction on bioactive
glasses and had positive effect on cell attachment.
Kim and Jee,75 studied the dependence of hydroxyapatite formation with respect
to crystalline phases in alumina-coated bioactive glasses. Hydroxyapatite
formation proceeded at a faster rate in samples containing α-wollastonite than in
β-wollastonite. The bioactive-glazed alumina showed much faster production of
20
hydroxyapatite than their corresponding bioactive bulk glass. Silica-rich layer was
absent beneath the newly formed HA in these crystallized bioactive glaze, as
opposed to the corresponding bioactive bulk glass that were capable of
producing such a silica-rich layer. Alumina-coated bioactive glasses are
considered superior to bulk glasses due to their faster rate of hydroxyapatite
formation.
Singh and Bahadur,76 demonstrated the synthesis and characterization of
structural and magnetic properties of different compositions of glass and glassceramics
in
SiO2.Na2O.CaO.P2O5.B2O3.Fe2O3
systems.
Glass-ceramics
containing a magnetic phase with glass matrix, were reportedly used as
thermoseed for hyperthermia treatment of cancer.52 The magnetic phase was
exposed to an alternating magnetic field, which generated heat due to loss of
hysteresis. This hyperthermia treatment is considered to be an effective
treatment for cancer especially bone tumors77 without side effects and this
process can be repeated many times after implanting a bioactive and
biocompatible ceramic within the body. A glass-ceramic with lithium ferrite
(LiFe5O8) and magnetite (Fe3O4) in an alumina - silica - phosphorus pentoxide
(AI2O3.SiO2.P2O5) glass matrix could be used as a thermoseed for hyperthermia
treatment of cancer.
The chemical composition of phosphate-based glasses is approximately similar
to that of bone, hence being potentially used as biomaterials. Franks et al.,78
prepared and studied phosphate-based glasses of the system CaO.Na2O.P2O5.
Thermal parameters were analyzed with differential thermal analysis. The
precipitation phases were identified by x-ray diffraction (XRD) and it became
evident, while one phase nucleated via bulk nucleation; the other nucleated via
21
surface mechanism by grinding the samples to different particle sizes. Systematic
study of the same system of glasses attempted to correlate the fiber production
with the network connectivity, interaction in chain length and glass cross-link
density and hereby affirming that changes in the phosphate content caused
alterations in temperature. A decrease in fiber solubility with an increase in the
calcium
oxide
content
was
also
concluded
thereby
reflecting
on
its
biocompatibility.79
Begum et al.,80 concluded that high content of silica in 1–98 bioactive glass used
in their experiment increased the hardness of the glass compared to 45S5
Bioglass® resulting in an attenuation loss, thereby increasing the elastic
properties of 1–98 (6Na2O, 11K2O, 5MgO, 22CaO, 1B2O3, 2P2O5, and 53SiO2)
bioactive glass, containing seven different oxides in it .
Also, alterations in
various elastic properties and changes in the bioactivity were brought about by
thermal treatments in these types of glasses.
Phosphate based bioactive glasses in addition to titanium dioxide (TiO2) studied
different parameters in the experiment. X-ray diffraction explored the amorphous
and crystalline nature of the material. The authors of the experiment concluded
that phosphate glasses with highest solubility became stiffer to degradation with
increased titanium dioxide content. Intense densification and interconnected
cross-linkages in the network was noted in glass structure by addition of titanium
dioxide. Chemical durability of glass-ceramics in de-iodized water purely depends
on the crystalline as well as the residual glassy phases that were formed. X-ray
diffraction analysis was used to investigate the formation of a biologically active
layer on the surface of glasses and glass–ceramics.81
22
Kasuga, in 200582 studied the calcium phosphate-based glass materials in the
pyrophosphate region. He noticed bone-like apatite formation on the surface of
these glasses when soaked in SBF at 1310 K. It was observed that calcium
pyrophosphate (Ca2P2O7) crystal formed in the glass-ceramics played an
important role in the apatite formation ability in SBF. In situ characterization of
thermal and structural properties in bioactive calcium phosphate glass-ceramics
was studied with addition of titanium dioxide and magnesium oxide. The heat
treatments at different temperatures from 954 to 998 K confirmed the
precipitation of crystalline phases in the glass matrix. Heat treatments at different
temperatures influenced the biocompatibility of the glasses.
In early 1990s, the advent of glasses with higher purity and homogeneity at
temperatures notably lower than those required to obtain glasses by melting were
produced by sol-gel processing.57 These bioactive glasses have supreme
bioactivity and resorbability in vitro, a quality required for the ideal bone graft
material.
Various research groups used the sol-gel processing to prepare bioactive
glasses for biomedical applications, not only in the ternary SiO2.CaO.P2O5
system, but also in the binary SiO2.CaO and quaternary SiO2.CaO.P2O5.MgO
system. In vitro studies showed that nucleation and crystallization rates of HCA
depended on many factors including the sol-gel glass composition.83
In his PhD thesis Greenspan,47 tested bioactive glass coated alumina implants
as load bearing prostheses in sheep. The results showed bone bonding but the
coatings were not stable.84 In an animal model, Gross85 detected that glassceramic spiked with potassium oxide and magnesium bonded to bone with a
mechanically strong interface. However, adding titanium and tantalum to the
23
glass composition prevented bonding. Additional histological analysis highlighted
the mechanism of bone bonded interfaces.48,85 The clinical use of this bioactive
material became restricted due to the instability of its crystal phase boundaries.85
A historically significant modification of Bioglass® was achieved by Yamamuro
and colleagues from 1985 to 1992.86-89 They successfully used apatitewollasotonite bioactive glass-ceramic in 3,000 cases of vertebral prosthesis,
12,000 cases of laminoplasty and 20,000 cases of iliac crest prostheses. Finnish
researchers at the Åbo Akademi University and the University of Turku proved
the effectiveness of bioactive glass as implant material, first in animal models,
then successfully for several years in head and neck surgery.90,91
In a very recent experimental effort by Lin and associates,92 they studied the
elastic properties and the structure of glass by maintaining the ratio of silica/
sodium oxide and decreasing the molar ratio of calcium oxide/ phosphorus
pentoxide. Raman spectroscopy and especially Brillouin experiments provided
intrinsic elastic properties for bioactive glass materials with specific composition
and phase. They exposed a very favorable nature of glass to display a more
polymerized silicate network which may prove influential or beneficial for bonding
of bone.92
6 Mechanism of Bioactive Bonding to Tissues
An aqueous solution when in contact with glass yielded both chemical and
structural changes as a function of time within the glass surface. 93 Both chemical
composition and pH of the solution were altered due to accumulation of
dissolution products. Soluble silica and calcium ions release in to the surrounding
tissue ensuing the formation of HCA on bioactive glasses are determining factors
24
in their rapid bonding to tissues, stimulation of tissue growth and their
consequential use as tissue engineering scaffolds owing to their mechanical
stability,
flexible
structural
changes,
bioactive
bonding
to
bone
and
bioresorbability.94-96
Eleven stages can be differentiated in the complete bonding process of
bioactive glass to bone. Stages i-v are chemical and stages vi-xi are
biological.17,41 Guy La Torre, at that time used newly developed FTIR analysis
technique for studying the molecular structure and its chemical bonds by
analyzing the absorption frequencies of the infrared spectrum in all five chemical
stages of the surface reactions as follows.17
Simplified chemical reaction stem:
i) Rapid exchange of sodium and calcium ion with hydrogen or oxonium (H3O+)
ions from the solution takes place (diffusion controlled with half-life dependence,
causing hydrolysis of the silica groups, which creates silanols) as: Si-O-Na+ + H+
+ OH-
Si-OH+ + Na+(aq) + OH-. The resultant hydrogen ions replaced by the
cations increases the pH of the solution.
ii) Hydroxyl concentration of the solution increases with cation exchange and
leads to the attack of silica glass network. Silicic acid, Si(OH)4 is formed as
soluble silica is lost, resulting from the breaking of Si-O-Si bonds and the
continued formation of silanols (Si-OH) at the glass solution interface proceeds
as: Si-O-Si + H2O Si-OH + OH-Si. This stage is a so-called interface-controlled
reaction
iii) Condensation and re-polymerization of silanols to form hydrated silica-rich
layer on the surface, depleted in alkalis and alkali-earth cations takes place.
25
iv) Calcium (Ca2+) and phosphate (PO43-) ions pass to the surface through the
silica-rich layer, forming a CaO.P2O5 - rich film on top of the silica-rich layer,
followed by growth of the amorphous calcium phosphate-rich film by
incorporation of soluble calcium and phosphates from the solution.
v) Crystallization of the amorphous CaO.P2O5 film by incorporation of hydroxide
and carbonate anions from the solution to form a mixed apatite layer finishes the
chemical phase of reactions.
In plain terms, there is dissolution of soluble silica from the bioactive glass when
the implant comes in contact with the body fluids. Leaching reaction takes place
with exchange of ions to form strong bonds under a time-controlled process.
Finally precipitation of ions takes place forming a bond between soluble calcium
and phosphates at the interface.97 A silica gel layer is formed which is quickly
covered by a calcium phosphate-rich layer. Cracks are propagated through the
outer calcium – phosphorous layer to allow phagocytic cells to penetrate and
partially resorb the gel.98,99 The noticed crystal phase change is manifested not as
an implant shape distortion or break, rather as an ongoing transformation at a
molecular level.9
Interfacial bonding with bone occurs because of the biological equivalence of
the inorganic portion of bone and the growing HCA layer on the bioactive
implant.96 The collagen fibrils and soft tissues are chemisorbed i.e., sub-class
of adsorption driven by a chemical reaction, via electrostatic mechanism at the
exposed surface on the porous silica-rich layer by ionic and/ or hydrogen
bonding. Hydroxy carbonate apatite is precipitated and crystallized on the
surfaces of collagen fiber and glass.100
26
Stages one and two of the chemical phase of reaction series are responsible for
the dissolution of a bioactive glass; hydrogen ions from the surrounding fluid and
alkali ions from the glass greatly influenced the rate of HCA formation. Many
studies showed that the leaching of silicon and sodium to the solution is initially
rapid, following the well-known parabolic relationship with time for the first 6 h of
reaction, and then stabilized following the so-called linear dependence on
time27,95,100-104 which influences the bonding of the implant material to the host
bone.
Then biological stages:
vi) Interaction of biological growth factors on the apatite layer and differentiation
of stem cells continues throughout the process.
vii) Phagocystosis by macrophages allows bone-forming cells to occupy the
space.
viii) Adhesion of stem cells on the bioactive surface.
ix) Differentiation of stem cells into osteoblasts.
x) Production of osteoblast generated extracellular matrix, osteoid.
xi) Enclosure of osteoblasts in a living cellular composite structure due to
inorganic calcium phosphate crystallization.
Reaction stages vi-xi are biologically mediated. The host cells perceive the
presence of the implant by initiating its degradation process. Silica gel starts to
disappear from the center through cracks and the particles become excavated.
The macrophages make room for the cells to remove the unwanted byproducts of
the reaction and allow the bone-forming cells, osteoblasts to perform their
function via in-growth of large undifferentiated mesenchymal cells that are later
differentiated into osteoblasts,105 providing collagen, ground substance and
27
matrix vesicles for primary mineralization and thus initiating a harmonious
chemical - biological series of reactions for new bone formation.106 Some in vitro
studies have exhibited a genetic control over the osteoblastic cell cycle in
bioactive glass particles with low levels of dissolution in a physiological
environment leading to rapid expression of genes that regulate osteogenesis.3032,107
Xynos and co-workers31 showed that a group of gene was activated within
48 h, including the genes encoding nuclear transcription factors and potent
growth factors, suggesting it to be a genetic mediated proliferative reaction of
bone.31 Insulin-like growth factors especially IGF-II, insulin growth factor-binding
proteins and proteases that cleave insulin growth factor from their binding
proteins were identified.30-32,107 The release of silicon stimulated the production
of transforming growth factor beta (TGFβ), an osteogenic cytokine promoting
rapid bone formation as they come in contact with the glass particle.108 Thus,
synthesis of growth factors and early activation of the various growth promoting
genes in a bioactive glass environment was shown to modulate the cell cycle
response of osteoblasts and the ionic dissolution products in these glasses.
These genes that regulate the cell cycle induction and progression can actually
enhance the osteogenesis as the come into direct contact with bioactive glasses.
However, osteoprogenitor cells only in a suitable chemical environment for
passing checkpoints in the cell cycle can synthesize a select number of cells from
this population that are capable of flourishing further by mitosis and becoming
mature osteoblasts.109
28
7 Factors Affecting Implant - Tissue Interface
It is of utmost interest that implants inserted into the body do not cause toxic
response to the surrounding tissues or cause systemic spread of toxicity. Table 1
provides a survey of various factors potentially affecting the implant - tissue
interface response. Implant anchorage into the tissue results in relative
resistance to infection110 and to a medium-strength mechanical strain.111-115
8 Composition - Reactivity Boundary
Bioactive glasses with the highest level of bioactivity and rapid bone bonding lie
in the middle of the Na2O.CaO.SiO2 region as illustrated in Figure 1.
All compositions contain a constant 6 wt. % of phosphorus pentoxide.
Composition in region A (i.e., bone bonding region) forms a bond with bone and
termed as the bioactive bone bonding boundary. Silicate glasses within region B
(i.e.,non-bone bonding region; reactivity too low), such as window, bottle, or
microscope slide glasses, cannot illicit a fibrous capsule at the implant - tissue
interfaces. Glasses within region C (i.e., non-bone bonding region; reactivity too
high) are absorbed by its surroundings and vanish within 10-30 days of
placement in situ. Glasses belonging to region D (i.e., non-bone bonding; nonglass forming region) are not technically possible and are therefore not been
tested as implants.104
9 Properties of the Material that Affect Bone Healing
Bone healing is directly proportional to the rate of dissolution of the implant
material in physiological surroundings, influenced by various factors. Various
ratios and addition of various compounds were used to adjust the dissolution
29
rate. It was found out that increased levels of calcium oxide, decreased
concentrations of sodium oxide, and addition of fluorine ions will slow down the
dissolution process of bioactive glass.91,116 Annealing is one aspect of the
manufacturing process that will affect the longevity of biodegradable implants
with higher temperatures, to slow down the degradation of calcium phosphate
fibers.107 Granulometry also influences the biological properties of bioactive
glass117 and ceramics118: smaller particles resulted in faster breakdown but
illustrated higher osteoconductive properties. Hence, aggregate combining
particles
of
different
sizes
could
potentially
benefit
from
prolonged
osteoconduction together with a simultaneous gradual degradation process.
Increased cohesion between particles proved advantageous to the biomechanical
properties of the commercially available glass, Corglaes® associated with it when
their size distribution follows the ideal linear logarithmic grading line.119
Degradation of grafting material, however, may be slower along a smooth, poorly
vascularized endosteal surface of repaired bone.120 Heterogeneity in vascularity,
osmotic fluxes and biomechanical loads may also influence the use of synthetic
grafting agents across different implant models and in clinical settings.121 Further
on, simultaneous incorporation of bioactive compounds in conjunction with
autogenous and allogenous bone grafts guide the process of osteogenesis.122
Bioactive materials can be used as local carriers of antimicrobial drugs and also
enhance hemostatic effect when mixed with tissue adhesives. To enhance
osseointegration, they can be combined with several adjunctive agents so far in
experimental use like specific bone morphogenetic protein, osteogenin, plateletderived factors, insulin-like factors, bone marrow cells and prostaglandin E1.9,123
30
10 Tissue Responses to Different Materials
The properties of various materials together with their tissue responses are
highlighted and elaborated in Table 2.
11 Composition and Commercially Available Products
Although a number of different compositions of glasses and glass-ceramics
were explored in the past, only a few of them have made it to the bench mark.
Food and Drug Administration (FDA), USA, approved compositions of bioactive
glass as highlighted in Table 3, whereas other compositions of bioactive glass
and glass-ceramics which are nowadays in experimental clinical use are
summarized in Table 4 in the annex part of this thesis.
12 Maiden Marketing
Having sufficiently established the properties of bioactive glass in vitro and in
animal studies, a research team of the University of Florida ascertained that this
promising material passed the necessary safety and efficacy tests.17 After
obtaining the ethical approval, they tested the material for the first time in humans
as middle ear prostheses and as augmentation material for the alveolar ridge.
After successful results in these studies, 45S5 Bioglass was deemed suitable for
commercial supply. The University of Florida accepted Bioglass and granted the
trademark classification Bioglass® to distinguish it from other bioactive glass and
glass-ceramic products being developed worldwide.17
The first Bioglass® device cleared for marketing in 1985 was the middle ear
prosthesis (MEP) trade marked as MEP® to repair conductive hearing loss. It
became popular because of its ability to bond both to hard and soft tissues in the
31
middle ear. Middle ear prosthesis outperformed other bioactive ceramic and
metal prostheses.124,125
Endosseous Ridge Maintenance Implant (ERMI®), in 1988 followed. They were
cones of 45S5 Bioglass placed into the extraction sockets to reinforce labial and
lingual cortical plates, and demonstrated outstanding stability and negligible
failure compared to other materials that had been used for the same purpose.17
Various clinical applications of Bioglass®, especially also in the head and neck
area are described in a paper from Hench et al.126
13 Clinical Applications
Glass in general, has been used in medical industry in a great variety: eye
glasses, diagnostic instruments, vials, tissue culture flasks, thermometer and
fiber-optics for endoscopy, to name only a few applications. Carriers for enzymes,
antibodies and antigens in the form of insoluble porous glasses 127,128 with a wide
array of applications owing to their high mechanical, thermal and chemical
stability, variable manufacture of pore sizes with a small pore size distribution and
variety of surface modifications are in used in medical practice. Versatility of
porous glasses in many different shapes proved
advantageous for various
application in industry, medicine, pharmacological research, biotechnology and
sensor technology.129 Resistance to microbial activity, pH changes, solvent
conditions, temperature and packing under high pressure have only added to its
advantage.
Glass and modifications have also been widely used in dental and craniofacial
applications as restorative materials130, dental abrasives131, dental implant
32
coatings132, cochlear implants133, bone substitutes or bone filler materials and 3dimensional bone tissue engineering scaffolds.134-137
14 Discussion
Bioactive glasses and glass-ceramics have evolved tremendously since its first
discovery by Hench in 1971. Bioactive glasses and bioactive ceramics or glassceramics are discussed synonymously in various occasions by authors and they
are not completely wrong; yet they are not exactly the same and exhibit variations
in
manufacturing
techniques,
composition,
mechanical
properties,
biocompatibility and bioresorbability, despite similar function of restoring or
replacing bone tissue. They have since displayed promising qualities of an ideal
non-metallic biomaterial.
The glass composition 45S5, containing 45% silica;
24.5% sodium oxide; 24.5% calcium oxide and 6% phosphorus pentoxide formed
the skeleton of other modifications that followed. Bioactivity of bioactive glasses
displayed superior capabilities with their ability to bond to bone and soft tissues
with a bioactivity index >8. Bioactive ceramics have a bioactivity index ranging
between 0 and 8 but unlike bioactive glasses, they only show osteoconduction.
Bioactivity of these materials start to unfold when contact with saline or blood
occurs. This cohesive environment can hold the particles in place until a new
apatite layer is formed on the surface of the implanted material within a certain
time. Biological mediators like collagen, mucopolysaccharides and glycoproteins
from the surrounding host environment initiated the bioactivity within the surface
of the implant when incorporated into the newly forming apatite layer. A direct
chemical bond in the presence of an aqueous medium of blood plasma or saline
results, initiating and facilitating early bone formation in the host. In vitro studies
33
showed strong interface of type I collagen adhering to glass particles being
embedded in the apatite layer.138 In vivo experiments100 showed an intimate
contact between the osteoid matrix and the glass implant. The apatite layer
stimulates osteoprogenitor cells to produce TGFβ, releasing silicon from the glass
surface and nurturing a favorable environment in the presence of osteogenic
cytokines to enable rapid proliferation of bone as they come into direct contact
with glass implant particles.108 As bioactive glasses are osteoconductive and
osteoinductive, they initiate the colonization of these osteogenic stem cells from
the host bone adjacent to the defective environment found prior to surgical
intervention.139 So far in the literature, the capability of these bioactive glasses
and glass-ceramics are well established. Limitations in various clinical
applications are dependent on the composition of the parent glass and its
manufacturing process which in turn reflect on its mechanical stability, bioactivity
and resorbability. These properties are critical in replacing bone in the load
bearing areas of the human body. Quite interestingly, the versatility of these
bioactive glasses caters to the various needs of its function in different sites
whether they are replacing bone itself or a composite structure consisting of bone
and soft tissues.
Another property, the size of the particulate glass granules influences bioactivity
of the bioactive glass and its rate of resorption.140 Granules size usually ranges
from 90-710 µm. An increase in the number of particles and decrease in the size
of particles would result in greater surface area of bioactive glass, thus offering
more sites for osteoblastic attachment and new bone formation.141 Conversely,
smaller particles are resorbed faster and replaced by host bone by its
osteoclastic activity simultaneously due to its multi-site action. This phenomenon
34
of characteristic and organized resorption and conserved osteogenic pouches
has been hypothesized to occur only in bioactive glass particles within a narrower
particle range.99 The bond strength of most bioactive materials at its interface has
been shown match that of normal bone.41,140 Failure under mechanical stress of
non-bioactive implants does not occur at the bone interface but rather occurs
within the biomaterial or in the host bone. A unique and prominent feature of
bioactive glasses that distinctly defines them as a promising material is their
performance devoid of failure at the bone interface 4 with the modulus of the
regenerated bone to be equivalent to normal cancellous bone after 4 weeks of
healing with its mechanical competency maintained through 12 weeks of
testing.141 The stability of the glass implants has been proven time and again to
be competent with its synchronized regenerative process; however failure within
the biomaterial under great force due to its brittleness and limited fracture
toughness could not be eliminated.
Animal study35 conducted on rabbit femurs showed that bone defects filled with
bioactive glass were replaced by host bone within 2 weeks as compared to
hydroxyapatite alloplastic material where bone replacement occurred at 12
weeks. While bone replacing bioactive glass was of trabecular structure, the one
replacing hydroxyapatite alloplastic material was detected to be a mix of nonresorbable material and composite bone. High cellular density and osteoblastic
proliferation rate with bioactive glass than with hydroxyapatite cements were
comparable to those found when autologous bone graft was used to repair
skeletal defects.36,142 Histological findings in a study in vitro143 elucidated that
osteoblasts from animal origin cultivated on bioactive glass were similar to the
amount in connection with autologous bone grafts with better osteoblast-like
35
morphology and a higher proliferation rate; still, better than in other implant
materials such as titanium, steel or hydroxyapatite particles. A comparison of
various synthetic bioactive materials has shown that bioactive glass produces
more bone than control materials like hydroxyapatite and tricalcium phosphate
during equal observation periods.144-146 Furthermore, it was detected when
performing Fourier transform infrared spectroscopic studies that, bioactive glass
was able to produce a bone morphology which was closer to natural bone than
the one produced while using hydroxyapatite.144 Their biological performance has
been proven by comparing them with autologous bone on various occasions, with
the advantage of no limitations in its supply.
El-Ghannam et al.,147 explained in their study that tissue fluid like blood, plasma
and extracellular fluid contains proteins that actively inhibit the formation of
hydroxy carbonate apatite layers; but simulated body fluid does not. The option to
create a HCA layer on the surface of bioactive materials is highly significant
because hydroxy carbonate apatite coated bioglass (BG-HCA) implants have
demonstrated an increased bone bonding ability by surface mineralization of the
bioglass in the presence of bone cells. The density of defects filled with HCA
coated bioglass continued to increase until it reached a maximum at 16 weeks,
and then decreased. On the other hand, unmodified bioglass (UBG) defects
continued to increase in its activity. These findings suggest that hydroxy
carbonate apatite properties in HCA coated bioglass implants facilitate material
degradation and phagocytosis, therefore accelerating the transformation of
implant material into host-similar bone in vitro.148 Another mechanism by which
surface-modified bioactive glass could achieve enhanced bone formation is
through its calcium ion release from the surface as supported by the works of
36
Matsuoka et al.148 Hence, we can come to an understanding that collaboration of
bioactive glass with similar bioactive materials was made possible with beneficial
outcomes.
Foreign body reactions have been noted with use of acrylates.149 The rise in pH
and osmotic pressure during the initial reaction of bioactive glass with host bone
in an aqueous medium discourages bacterial colonization amongst the oral
microorganisms Actinobacillus
actinomycetemcomitans,
Porphyromonas
gingivalis, Actinomyces naeslundii, Streptococcus mutans, and Streptococcus
sanguis.150 The combined effects of bioactive glass, hydroxyapatite and the oral
microorganisms were studied experimentally.151 Stronger bond and bacterial
establishment were found on the surfaces of hydroxyapatite.151 However,
bioactive glass did not favor the adhesion of either Haemophilus influenza or
Streptococus pneumoniae.151,152 In addition, bioactive glass does not favor the
growth of a wide range of aerobic and anaerobic bacteria in general, which can
promote a reliable clinical outcome.153-156 The use of synthetic materials instead
of allogenic or animal-derived graft materials decreases the likelihood
of
biohazard infections97 and disease transmission, which is one of the key
prerequisites for an ideal option of a graft for replacing bone or soft tissue.
Some forms of bioactive glass scaffolds like the plates are standard pre-formed
structures that are brittle and rigid, and cannot be molded, shaped, or fixed with
screws by the operator and pose as big challenge to them.97 It is indeed a major
setback for the bioactive glass scaffolds due to the inflexibility of its handling
properties unlike other biomaterials like poly methyl methacrylate (PMMA), but
hopefully with meticulous planning and further research to combat such
37
drawbacks bioactive glass and glass-ceramics will certainly evolve as a premier
choice of graft substitution.
38
Part II
Bioactive Glasses in the Cranio-Maxillofacial and Oral Surgery
– Evidence Based Review
39
1 Abstract
Introduction: Critical size bone defects are impossible to heal on its own creating
a gross deformity and almost always required bone grafting. Although autologous
bone represents today’s gold standard option, recent advances in technologies
have offered a variety of choices including allografts, synthetic osteoconductive
scaffolds, growth factors, osteoprogenitor cells and distraction osteogenesis for
bone augmentation and reconstruction.
Aims and Objectives: No randomized controlled trials till date have compared the
performance of bioactive glass with other conventionally used biomaterials. The
main purpose of this evidence based review is to assess and evaluate the
efficacy of bioactive glass in cranio-maxillofacial surgery.
Materials and Methods: Electronic database including Pubmed, Embase and
Cochrane were searched from the earliest available to October 2011. The search
was restricted to the English language articles and yielded 442 articles which
were brought down to 267 after the removal of duplicates electronically with
EndNote and double-checked manually afterwards. Seventeen articles were
excluded and 250 articles fit the inclusion criteria for abstract screening.
Seventeen articles pertaining to the cranio-maxillofacial region was chosen after
scrutiny. One article had to be excluded later as the findings were unsuitable for
inclusion, thus finally ending up with 16 articles.
Results: Selected articles were published between the years 1993 and 2012.
Seven prospective clinical trials, two review articles, two retrospective case
series, two randomized controlled clinical trials and one prospective randomized
clinical study, prospective case series and case control study each was selected
for the final review. Only two randomized controlled clinical trials comparing
40
bioactive glass with autogenous bone and un-grafted site was found; none
compared the efficacy of bioactive glass with other biomaterials used in the
literature. Concisely, all studies exhibited positive results in the long-term, well
accepted by the subjects with minor short-term complications like infection
amongst others. Re-operations done for the above or other reasons were
unrelated to the bioactive glass used.
Conclusion: We have limited literature and clinical experience for extensive facial
skeleton augmentation with bioactive glass over other pre-fabricated implants. It
is therefore necessary to develop an evidence based biomaterial specific guide
line and algorithm for its clinical use. A protocol for bioactive glass may prove
useful in choosing this material for craniofacial reconstruction with ease.
41
2 Introduction
Our skeletal framework consists of bone, a very unique composite tissue that
supports its form and function. Its continuous remodeling process may be
hindered by various aspects. Bone defects, exceeding the critical bone size
defect may occur directly due to trauma, infection, tumor resection and skeletal
abnormalities such as phacomelia, polyostotic fibrous dysplasia, osteogenesis
imperfect and metaphyseal dysplasia to name a few, necessitating definitive
treatments like amputation or resection with surgical correction. Other bone
defects may occur because of compromized regenerative processes such as
avascular necrosis, atrophic non-unions with little or no callous formation,
sclerosis or sealing of medullary cavity at the site of bone discontinuity and
osteoporosis. Critical bone defects are the smallest size intraosseous wound that
will not heal spontaneously during a life time. 157,158 Such bone defects are
impossible to be restored only by physiological processes without creating a
gross deformity and often bone grafting is needed. Critical size bone defects 5-8
mm in length is considered to fulfill the criteria and were tested on various animal
models in the literature.158,159 Autologous bone of vascularized and nonvascularized origin; either fresh or preserved represents today’s “gold standard”
in bone grafting techniques.1
Recently,
thanks
to
advances
in
research
technologies,
allografts,
osteoconductive scaffolds, growth factors, osteoprogenitor cells and distraction
osteogenesis have entered the field of bone augmentation.160
Each of these procedures bears its own advantages and disadvantages. Tissue
engineering and gene therapy161 for improved local scheme of treatment or even
systemic enrichment of bone with dietary supplements,162 are under intense
42
scrutiny in order to overcome the constraints of current methods. In the field of
bone substitutes there is a big ongoing competition to facilitate alternative
production of materials with biomechanical properties as much indistinguishable
from normal bone as possible.
When in need of bone grafting, one must understand the different available
options of bone replacement to decide what best caters to the need. With the
evolution in biomaterial research, smart bone substitution materials were
classified into first, second and third generation materials.43 Evolution in
biomaterials by 1980, had more than 50 implanted prostheses in clinical use
made from 40 different materials which were biologically inert.163
According to Hench’s classification163,164 those biomaterials developed during
the 1960’s and 1970’s which had physical properties matching those of the
replaced tissues and showed minimal toxic response to the host organism were
called first generation. These biomaterials were ‘inert’ having minimal foreign
body reactions and immune responses when implanted within a living organism.
Some examples are titanium with its alloy metals, stainless steel, ceramics and
polymers.
Biomaterials of the second generation unfolded since the 1980’s. They are
defined as bioactive materials that are capable of eliciting interactions with the
biological environment thereby enhancing the biological response and the tissue surface bonding, and simultaneously undergo progressive degradation during the
healing process.163,164 The term bioactivity refers to the behavior of materials with
the surrounding cells or tissues leading or activating them to specific responses
or outcome. Mineralization and deposition of an apatite layer in the bone –
implant interface is one of the most currently known processes to maximize
43
bioactivity in bone rehabilitation. Most common materials in this second
generation
are
bioactive
glasses,
glass-ceramics,
calcium
phosphates,
hydroxyapatites and their derivatives.163,164
Among these materials, the component silicon plays a vital role in the
production of new bone. Silicon is involved in the calcification process of young
bones and their suggested mechanism of action is manifold, including the
collagen production and/ or its stabilization and matrix mineralization.165 Thus,
osteogenesis in the presence of silicon in bioactive ceramics and glasses play a
significant effect in this process. Factually, incorporation of silicon into apatite
increases the amount of bone tissue compared to materials in its absence.
Moreover, silicon improves the bioactivity leading to formations of Si–OH groups
on the material surface. These groups improve the nature of the material - bone
bonding by triggering the nucleation and formation of apatite layers on the
surface.164
According to Hench’s classification, materials able to stimulate specific cellular
responses at the molecular level belong to the third generation. These
biomaterials are bioactive, biodegradable and bioabsorbable. The ability to signal
and stimulate specific cellular activity and behavior in the host should match the
properties of the bioactive material.164 Recently, cell invasion, attachment and
proliferation in temporary three-dimensional porous structures with functionalized
surfaces
containing
peptide
sequences
mimicking
extracellular
matrix
components to instigate specific cell responses are under intense research and
development.164 Further fields of research interest represent biochemical factors,
medical drugs, and control of cell behavior using mechano-transduction.163,164
44
Bioactive glasses and glass-ceramics are successfully used in various clinical
applications. The first ever bioactive glass was discovered by Hench et al., in
1969.17 In 1971, the first ever paper based on the in vitro and in vivo results with
bioactive glass was published.19 The first commercial bioactive glass has been
available for clinical use since the early 1980s’.17 The first generation of bioactive
glasses, of which Bioglass® was the first product on the market, were used
successfully in the treatment of conductive hearing loss in the name of middle ear
prosthesis (MEP®).17 Since then continuous research has improved the abilities of
bioglasses and various combinations of materials with superior properties have
been investigated, as elaborated in Part I.
Even though clinical applications in different case series 97,106,166,167 yielded good
results, no single randomized control clinical trial comparing the performance of
bioactive glass with conventionally used bioactive materials like hydroxyapatite
amongst others exists to date. However, two randomized clinical control trials
comparing bioactive glass with autologous bone105 and nil graft168 respectively
was found during the literature search.
The purpose of this evidence based review of the literature is to thoroughly
investigate clinical studies where bioactive glasses was used to augment,
obliterate or replace bone in cranio-maxillofacial and oral surgery and to assess
their clinical outcomes.
3 Materials and Methods
Electronic database including Pubmed, Embase and Cochrane were searched
using the following key words from the earliest available to October 2011 and
thereafter arbitrarily:
45
(#1) AND (#2)
#1 – clinical studies, human clinical trials, head and neck, reconstruction, clinical
application, craniofacial surgery
#2 – bioactive glass
The search was contained to the English language articles only. The year of
publication was unrestricted. The search strategy was devised in agreement with
both the supervisors and guided by the librarians of our faculty.
All citations were retrieved unmodified and exported to the EndNote X4
(Thomson Reuters; Carlsbad, California) bibliographic management software.
Duplicates were removed in two stages electronically using EndNote and
manually. Abstracts of all the remaining articles were screened and unrelated
articles were categorized and eliminated. Full text articles related to the review
were obtained and re-screened for eligibility along with both the supervisors.
Inclusion criteria are all clinical studies conducted in the cranio-maxillofacial and
oral regions on human subjects. Reviews with parallel histopathological/
radiological studies were included however one article thus obtained was
excluded based on its non-independent comparison of results between human
and animal subjects. No specific age criteria or number of subjects were
incorporated into the elimination process. All other than English language articles
and articles whose full text could not be retrieved were also eliminated from the
study.
Each of the remaining full text articles were re-screened along with the two
supervisors and the final set of articles for statistical analysis were finalized.
46
Flow diagram of study selection procedure
47
3 Results
The initial searches for our evidence based literature review yielded an overall
of 250 articles and were categorized according to the various sites involved. As
the target of the here presented study was the cranio-maxillofacial and oral
region, seventeen articles fulfilled the inclusion criteria and were accepted for
review. The article of El-Ghannam et al.,147 had to be excluded later because the
authors compared findings between human and animal subjects.
All selected articles were published between the years 1993 and 2012. A total of
16 studies could be finally included in this review: seven prospective clinical
studies,9,99,151,169-172 two reviews articles,173,174 two retrospective case series,97,106
two randomized controlled trials105,168 and one each of prospective randomized
clinical study,109 prospective case series166 and case control study.175
There were three studies performed with controls.105,168,175 Two of these studies,
Throndson et al.,168 and Tadjoedin et al.,105 used the split mouth technique.176
Only two of sixteen studies were randomized controlled trials.105,168 The third was
a prospective randomized clinical study109 performed without controls.
Due to limited data, insufficient and non-standardized parameters measured in
each of the included studies; it was not possible to perform sophisticated
statistical analysis.
A clear-cut criteria for successful outcome was defined by Gosain et al.,173
with objective evaluations of: i) absence of post-operative infection and ii) nil
exposure or dislodgement of the implant; and subjective evaluations of: i)
preservation of optimal contour and ii) treatment outcome by patient and surgeon.
Lack of such standardized parameters across different studies made it difficult to
perform statistical analysis of the outcome measures.
48
In short, all studies exhibited positive results in the long-term for bioactivity of
bioglass used for augmentation with minor short-term complications like infection
and re-operation for the same or other reasons.
However, summary of results across various studies and results of individual
studies are elaborated below for a better understanding of the clinical outcomes
of these studies and to emphasize the purpose of this evidence based research.
Six of the included articles did not mention the duration.99,105,151,166,171,175 There
were big variations between the numbers of participants among all the included
studies. The study99 with the maximum number of subjects was eighty seven and
the minimum number was four.169
An age range from 5.5 to 79.0 years was recorded across all covered studies;
however, no gender predilection was specified.9,97,99,105,106,109,151,166,168-175
Bioactive glass was inserted in locations of the cranio-maxillofacial and oral
region, such as the frontal, parietal, temporal, occipital, malar, orbital and alveolar
bone; and cavities like the frontal and maxillary sinus. In these locations bone
defects were either congenital or secondary due to trauma or pathology. The
exact size of bone defects were not clearly defined by most authors. Some of
them reported linear measurements,97,151,169-171,173,174 while others did not. None
mentioned unique or special surgical techniques, like a particular authors’ version
or modification of a surgical method and all operations were carried out using
standard surgical protocols for facial skeleton contouring, augmentation,
reconstruction of various bone defects in the craniofacial and oral regions, and
obliteration of sinus cavities.
In ten9,97,105,106,109,151,168,170,173,174 of the sixteen included papers, operators used
commercially available products like Nova Bone® Jacksonville, Florida; Bioactive
49
glass (BAG) plates and granules from Abmin Technologies, Turku, Finland;
Vivoxid Ltd., Turku, Finland; Biogran®, Warsaw, Indiana; BAS-0 from Lasak Co.,
Prague, Czech Republic; Perioglass® (Nova Bone®) Jacksonville, Florida; S53P4
bioactive glass implant from Abmin Technologies, Turku, Finland and S45P6
bioactive glass particles from FBFC International, Belgium. The custom made
materials were applied by two authors166,171 and were of S53P4 variety with a
composition of silica - 53%, calcium oxide - 20%, sodium oxide - 23%, and
phosphorus pentoxide - 4%.
Schepers et al.,99 used a single product throughout the experiment supplied by a
Belgian company, FBFC International with the 45S5 Bioglass® composition of
45% silica, 24.5% calcium oxide, 24.5% sodium oxide and 6% phosphorus
pentoxide by weight of granules. It is only by them amongst others122,151,169 who
quoted the particle size of bioactive glass and also reported its effect on clinical
outcomes. The particle size of the material ranged 300-360 μm.
Mean
implantation time in entirety was 25. 4 months. The operators found it easy to
handle the bioactive glass particles of narrow size range at the time of insertion
and deciphered that it also influenced the healing with selective resorption
phenomenon. The glass particles were maintained within the grafted site when
meticulous primary closure was obtained. There was no loss of material noted on
follow-up. On post-operative clinical examination, the operated site appeared
solid. Minor changes in contour of Bioglass® were noted up to 2 months after
surgery and stabilized from 3 months. Radiographic analysis showed integration
of the grafted material in the bone lesions. Radiographic difference between the
glass particles and bone nearly disappeared after 6 months of surgery. During
the initial phase of the study, several complications arose, none of which were
50
related to the product used and was overcome by altering the surgical technique.
Failures were caused by insufficient filling in some cases of thirty apical
resections. Partial loss of the material was encountered due to inadequate soft
tissue cover in eight of forty patients who underwent extraction with grafting
immediately post-extraction in these sites; and four of twenty patients who had
correction of alveolar ridge for prosthetic reasons. Infections were noticed in
patients who were treated for apical resections and cyst enucleations, probably
due to the pre-existing pathology. The overall clinical evaluation was generally
satisfactory.
Dušková et al.,9 assessed the biocompatibility of non-metallic non-resorbable
oxyfluoroapatite-wollastonite based surface-active inorganic polycrystalline glassceramic. They studied the effectiveness of this material for use in facial recontouring in forty-four patients with post-traumatic defects, post-tumor
resections and various syndromes. Results of this study showed uneventful
healing without any complications. Nil reported infection. There were sufficient
contacts between the implant and bone tissue on radiographic interpretation, and
touch stability was achieved within six weeks. One side-effect of the operation
was a large hematoma formation which was unrelated to the material used. One
case of long-term complication was extrusion of the material in an irradiated area
of maxillectomy with the median time of extrusion to be five months. The cause
was attributed to the poor quality of soft tissue coverage over the implant due to
pre-existing defective tissue over the irradiated area. They did not note any real
bond between the implant and bone during re-operation. The changes of the
extruded implant were studied using EDS, WDS and XRD. Though the exact
mechanical features of the implant could not be defined, they found a change in
51
the material’s crystal structure after human exposure with no fracture or shape
instability noted. There were no signs of degradation or pathological reaction from
the adjacent tissue.
Norton and Wilson109 compared the effects of Perioglas® or Biogran® randomly
chosen for their patients who underwent extraction of teeth for various reasons
and immediate socket preservation with one of the two above mentioned
materials available on the commercial market. They maintained a mean time of 6
months between the augmentation and placement of dental implants in the
extracted site. Six patients received Biogran® in 18 sites and twelve patients
received Perioglas® in 21 sites. Six out of eighteen patients received Gore-Tex®
barrier membrane after augmentation of the dental extraction site. Unfavorable
clinical scenario of the grafted material with intense reddish color and rubbery
consistency was noted in four patients. Two of these four patients experienced
severe
unremitting
and
uncharacterized
pain
after
implant
placement
necessitating its removal for complete resolution of pain. Failure was observed in
one of these four patients who lost 3 out of the 4 dental implants that was placed
and who was subsequently diagnosed with colon carcinoma, which the authors
attributed to the reason for loss due to immuno-compromized status of the patient
at the time of implant placement. Two patients experienced infection at the
implanted site due to exposed membrane, necessitating its early removal
followed by resolution with antibiotics. One patient died during the course of study
with 5 successfully installed dental implants fully functional at that time. Mixed
responses were recognized on histological analysis. Evidence of inflammatory
infiltrate was viewed in the biopsied specimen of one patient probably related to
the remnant inflamed periodontal tissue and not actually due to the bioactive
52
glass used. New bone formation was not appreciated in specimens harvested
within 6 months and a consistent appearance of bone of mixed woven and
lamellar quality was seen only after 6 months of healing. Characteristic bioactive
glass reactions were seen on these specimens but the histopathologist could not
distinguish between the two materials under the light microscope.
Cordioli et al.,170 evaluated the performance of Biogran® combined with
autogenous bone in their non-randomized, prospective, II stage clinical study of
bone augmentation at the maxillary sinus floor with immediate implant placement.
Twelve patients with 3-5 mm of bone from the residual edentulous alveolar crest
unilaterally or bilaterally underwent augmentation with 70-80% Biogran® and 2030% particulate autogenous bone taken from the maxillary tuberosity or
mandibular symphysis and mixed with blood coagulum.
Intra-operative
complications of sinus perforation resulting in nasal bleeding were witnessed in
two patients. None had complications except anticipated edema and erythema at
the surgical site after operation. All implants were firm at the time of replacing the
abutments 10-12 months post-operatively. A single implant failed during the
prosthetic phase. Marginal bone resorption not exceeding 1.5 mm was measured
from the abutment at 12 months. Computed tomography (CT) scan results
showed dense mineralized material in the sinus cavity surrounding the implant.
Most cases had no clear demarcation between the augmented bone and the
sinus floor. A mean increase of 5.5-8.7 mm of bone height was measured 9-12
months after augmentation. Histological and histomorphometric examination from
7 grafted sites in 6 patients showed bone, osteoid, fibrous tissue and transformed
Biogran® particles. The regenerated bone was predominantly woven bone with
well-vascularized connective tissue in their marrow spaces. Remaining non-
53
disintegrated glass particles were well incorporated into bone in most of the
specimens although some showed fibrous connective tissue in the deeper
locations. Osteoid was identified at the excavated sites of bioactive glass in the
centre and periphery of the restored defect. Only scarce autogenous graft
particles were visible at the grafted sites.
Post-operative radiological analysis was performed with CT scans97,106,151,169-175
and
plain
radiographs;9,97,99,105,106,109,168-170,174,175
histological
analysis;97,105,109,151,166,170,171,173 in addition to clinical correlation9,99,168,169,171,174,175
were included as a part of the follow-up method in the included studies of this
evidence based review.
Computed tomography to assess the stability and position of implants in the
form of plates and scaffolds;97,169,174,175 new bone formation;169,170,175 density of
bone at the implanted site;166,170-174 loss of implant volume or loss of volume of
the obliterated cavity97,106,151,174,175 and relapse of disease.106 MRI and PET scans
were done in cases suspected of tumor recurrence in the reconstructed site 106 or
for assessing signs of activity of new bone formation at the bone defect margin
and the implant and was deduced to be of good clinical outcome for BAG-PMMA
implant as observed by the authors of this study.169 Plain radiographs were used
for the same purpose; but with less precision compared to CT scans.
Peltola et al.,171 studied the efficacy of frontal sinus obliteration with bioactive
glass in ten consecutive patients experiencing chronic frontal sinusitis unresolved
by other conservative treatments. The bioactive glass granules and blocks used
in this study were handled with ease. Good obliteration was accomplished in all
participants of the study. Three patients had persistent frontal pain, six patients
suffered supra-orbital neuralgia and three had supra-orbital paresthesia at 3
54
months post-operatively and diminished with time. Only one patient each with
supra-orbital neuralgia and supra-orbital paresthesia presented at 36 months
post-operatively. Unsatisfactory outcome was recorded in no one. Nine patients
exhibited unremarkable findings on sequential CT examination.
Granulation
tissue at the site of previous trephination and local inflammation was noted in
one. Re-obliteration with bioactive glass showed complete asymptomatic healing
through 3 years after the therapy. The morphological analysis with CT images
showed stable bioactive glass substance. Histological samples taken at the time
of plate removal in two patients showed dense fibrous tissue in the absence of
new bone formation between the glass particles. Thick reaction layer was
accumulated on the surface of bioactive glass devoid of inflammatory or foreign
body reactions.
Peltola et al., in 2006151 filled the frontal sinus using bioactive glass without a
clinical control in this long-term study having previously proven success of the
same material in a 5 year study reported in 1998.171 Forty-two consecutive
patients with chronic supparative frontal sinusitis treated by osteoplastic frontal
sinus obliteration previously were enrolled in this study. Three out of forty-two
patients did not have any previous surgeries and the number of previous
operations in the remaining patients ranged from 1-6. Bioactive glass granules of
sizes 0.5-0.8 mm and 0.8-1.0 mm were used for obliteration and the largest
defect treated was 2.5 cm2. All patients had a variety of symptoms before this
operation including chronic frontal pain. At 3 months after the surgery, 10 patients
complained of neuralgic pain over the supra-orbital region and 7 patients
complained of chronic frontal pain. Intense frontal pain was relieved by the
current operation with satisfactory cosmetic results at 12 months. Delayed wound
55
healing was noted in one patient up to 12 months post-operatively due to basal
cell carcinoma in that region, which improved after wound revision. Two subjects
had persistent post-operative neuralgia or paresthesia at the supra-orbital region.
No one expressed dissatisfaction of the treatment. CT scans of all recruitees
performed post-operatively at 1 week, 6 months, 12 months and thereafter
annually were found intact in the absence of loss of volume. Region of interest
(ROI) evaluation in 30 patients performed from the middle of the BAG obliteration
displayed a decrease in Hounsfield units (HU) between 1 week and 24 months
which continued to decrease up to 48 months. There was stable increase in HU
thereafter recorded up to 84 months, with only minor variations observed after 12
months of evaluation. Histological analysis of five patients in total were done, two
who reported of discomfort caused by the fixation screws, one patient who had
delayed wound healing due to basal cell carcinoma and two patients who
underwent re-obliteration due to mucocele formation. Findings assured new bone
formation with less scattered fibrous tissue at 104 months and 120 months
versus 60 months post-operatively. There was no inflammatory or foreign body
reactions noted. Scanning electron microscope confirmed new bone formation
with bioactive glass granule covered by a calcium phosphate layer at 104
months. Analysis of bone quality by Fourier transform infrared spectroscopy
perceived bioactive glass infested bone to be similar to that of natural frontal
bone. Microbiological cultures produced no bacterial growth.
Suominen and Kinnunen175 applied bioactive glass granules and plates in 13
patients at 36 sites for facial bone reconstruction. Sixteen sites in the same
patients were treated with autogenous graft from the parietal bone and iliac crest
bone was used in one patient. The glass plates were of the following dimensions:
56
8 x 10 mm; 15 x 29 mm; with 1.5, 2.0, 2.5 or 3.0 mm thickness. Holes drilled on
the plates aided fixation. They were incorporated in 20 sites. Glass granules were
implanted at 16 sites. The follow-up period was for an average of one year. The
glass plates retained their original size. A reduction in the glass granules and
autogenous bone grafts not exceeding 50% were noted in both groups. There
was no change in the bone density at the grafted sites within six months. A
sparsity of glass granule implants by 29% was noted between 1 week and 6
months. One patient with orbital wall reconstruction was re-operated due to
improper implant positioning and thereafter the healing was uneventful. Purulent
maxillary sinusitis and wound infection troubled one patient. Treatment with
antibiotics and subsequent removal of titanium plates 6 months later resolved the
problem. Bacterial culture did not encourage the growth of pathogens; however,
granulation tissue was noted at the affected site. One patient presented with
diplopia both pre- and post-operatively and the condition was unchanged after
the current surgery.
Peltola et al., in 200897 treated forty-nine patients with complex craniofacial
trauma and tumor reconstruction involving the orbit with the size of the largest
defect being 2 cm. Forty-one patients underwent reconstruction involving the
orbital wall post-trauma and eight patients for reconstruction post-tumorectomy
using bioactive glass plates. Three patients were lost to follow-up and three
patients had defaulted after 6 months in this two-year study. Diplopia and infraorbital nerve paraesthesia were the most common pre-operative symptoms. Postoperative diplopia was seen in 5 patients and enophthalmos in 4 patients. Postoperative assessment with either only CT scans or along with sinus radiographs
showed well retained orbital floor or wall reconstruction in all except 8 patients
57
due to extensive loss of orbital bone structures. Three patients had re-operations
in total. Two for diplopia at 3 months and 6 months respectively and one for pain
two years post-operatively. The bioactive glass plates in these patients were
found intra-operatively to be of incorrect anatomical shape and size. Satisfactory
outcomes were achieved after repeated reconstruction with the appropriate-sized
plates. CT scans assessed up to 2 years post-operatively revealed no signs of
resorption on the margins of the bioactive glass plates. Histological studies
revealed slight new bone formation 2 years post-reconstruction on the lower
surface of the bioactive glass plates along with typical reaction layers seen in
bioactive glasses with only minor resorption on the glass plates. In tumor patients
early post-operative complications were seen in one patient with cerebrospinal
fluid (CSF) leak and two patients with meningitis, all treated successfully. Longterm complications of diplopia were seen in 4 patients; and two of them had
enophthalmos and trigeminal nerve dysfunction. None required re-operation. The
most common complication for tumor patients was olfactory nerve lesion in all 8
patients resulting from the surgical approach.
Gosain et al.,173 compared the use of various bioactive material in twenty-five
pediatric patients with a mean age of 5.5 years. The mean follow-up period was
3.3 years. Hydroxyapatite was used in 5 patients; calcium phosphate was used in
3 patients; bioactive glass was used in 3 patients and demineralized bone in 8
patients. Onlay augmentation in eight patients used hydroxyapatite and calcium
phosphate. Inlay reconstruction was done in eleven patients using bioactive glass
and demineralized bone. The maximum width of cranial defect reconstructed with
bioactive glass was 5 cm. In three out of the eight patients treated with
demineralized bone, the defect exceeded 5 cm.
58
Additionally, pre-fabricated
porous polyethylene was used in six patients; 3 for malar augmentation and 3 for
inlay calvarial reconstruction. Well augmented bone without relapse or growth
abnormalities was confirmed with photographic evidence in all patients who
underwent treatment with the use of hydroxyapatite or calcium phosphate.
Persistent skeletal augmentation and bone density at the grafted site was noted
to be equivalent to that of normal adjacent bone on CT evaluation. Solo
complication of post-operative infection was noted in this group, necessitating
partial removal of the implant. Hydroxyapatite onlay was biopsied during a repeat
surgery for a neurological procedure.
It was observed that there was good
incorporation of the implant with new bone formation at its periphery in the
absence of any in-growth within the implant. Photographic evidence showed
successful skeletal re-contouring in all patients with the use of bioactive glass or
demineralized bone. CT scans taken 1 year later indicated varying degrees of
bone density but satisfactory bone mineralization in 9 of 11 patients across the
entirety of the defect. No residual contour defects were noted post-operatively in
this group. CT scans taken for patients who underwent treatment with
demineralized bone paste supported by resorbable plate were found to be
unchanged in position and also showed progressive mineralization of calvarial
defects in one year’s time. The most consistent favorable outcome of the
demineralized bone group was noted in a patient with 8 cm cranial defect of the
temporal fossa which required in addition, a reconstruction with temporalis
muscle flap. Repeat surgery in the demineralized bone group was performed due
to inadequate mineralization at the periphery or within the reconstructed defect
requiring adjustment of the palpable titanium mesh or reconstructing the defect
with demineralized bone struts. Residual defects less than 1 cm noted on CT
59
scans were not of clinical importance. Pre-fabricated polymers were used in six
patients in total; 3 for onlay malar augmentation and 3 for inlay calvarial
reconstruction. Excellent clinical outcome was achieved for correction of right
cheek recession in this group. The bone density at the experimental site never
reached that of the adjacent normal bone on review CT scans. One patient
experienced peri-implant infection successfully treated with serial irrigations,
drainage and intravenous antibiotics. Overall results were successful in these six
patients belonging to this group.
Peltola et al., in 2012169 reported the clinical outcome of a custom made
composite bioactive material in craniofacial reconstruction of four patients. The
scaffold material was hand-made with poly methyl methacrylate (PMMA) coated
with bioactive glass granules on both the bone surface and overlying tissue with
perforations made on it to enhance tissue in-growth. The position of the implant
was stabilized with a 1 mm screw. Progressive uneventful healing was noted in
all cases from early post-operative period up to 3 months. The implant position
appeared unchanged during clinical and radiological examination. Scans done
revealed unchanged implant position with impression of new bone formation two
years after the operation. All three calvarial reconstructions exhibited good early
and late aesthetic and functional outcomes and a satisfactory outcome with
orbital reconstruction. A single unrelated complication to the implant was epidural
hemorrhage in one of the patient’s with skull bone reconstruction.
Aitasalo et al.,174 studied the clinical outcome of rigid bioactive glass implants of
3 sizes in reconstructing orbital wall fractures in 36 patients. Twenty-eight out of
36 patients had one year follow-up. Six patients had only 6 months follow-up and
two patients failed for the review visits. The size of the defects ranged from 1-2
60
cm. Seventeen patients presented with diplopia, nine with enophthalmos, and
three each had vertical dystopia and intraocular pressure over 25 mmHg preoperatively. Visual acuity was normal in all but one patient post-operatively. The
visual acuity was scored 0.3 in that patient, which was caused due to previous
cataract problem. Optical test with Hess chart revealed diplopia in four patients
but only two had it when tested with red-green glasses. One of the patients had
persistent esotropia even after strabismus operation along with enophthalmos
and diplopia. Two patients had dystopia post-operatively, one graded mild and
the other severe. Partial infra-orbital nerve paraesthesia was noted in 5 patients
post-operatively. Two patients had optic nerve damage with visual field defect.
Symblepharon due to transconjunctival approach was seen in 2 patients.
Radiological assessment of the graft showed adequate maintenance of orbital
floor and maxillary sinus volume with partial deformation of sinus in 4 patients
with complicated maxillary trauma. Infection was absent and new bone formation
at the anterior wall of the operated maxillary sinus on axial views was evident.
The bioactive glass implants showed no signs of resorption and appeared the
same both immediately and 1 year post-operatively. Nil reported cosmetic
deformity, infection, rhinosinusitis, haemorrhage, extrusion or displacement of
implant post-operatively or on long-term basis. One case of improper positioning
of implant was re-operated due to complaints of diplopia. Three patients had
enophthalmos and one had entropion. The overall cosmetic results at one year
were reported to be good.
Throndson et al.,168 analyzed the clinical outcome of randomized third molar
grafted sites with Biogran®; their controls were non-grafted. Twenty patients were
initially enrolled but six were lost to follow-up. Statistically significant difference in
61
the clinical attachment level was noted with mean gain in the attachment level of
the grafted sites and mean loss in the non-grafted sites at 3 months. At 12
months the results were still significant between the two groups with the grafted
site having smaller loss of attachment level compared to the non-grafted site.
There was no significant time effect. Radiographic changes showed no prominent
difference between the grafted and non-grafted sites. The authors came to the
conclusion that although routine use of bioactive glass may not be suggested, a
consideration to graft deeply impacted third molar sites to improve the periodontal
status of second molars may prove valuable. Incidental findings of less postoperative pain in the immediate post-operative period were reported by all of the
20 blinded patients for the grafted site. Three cases of localized osteitis occurred
and were treated in the non-grafted sites. These reports need to be further
investigated due to the small sample size and the inconclusive benefits.
A single study underwent parallel in vitro analysis in simulated body fluid and
Tris solution.166 Bioactive glass masses were tested in these two solutions for
resorption of silicon and phosphorus ions. This, the author deduced will help to
assess the reliability of the difference in rate of resorption of the glass granules of
different sizes. Peltola et al., in 2001166 also declared in his results that the noted
infection in one of the specimens tested for microbiology was probably not
influenced by the bioactive glass reactions and in principle is likely to be seen in
clinical scenario as well, but were considered minor. A conclusion was arrived
stating bioactive glass to be a stable, durable and safe material for massive filling
of frontal sinuses and a follow-up model by measuring the clinical variation of
Hounsfield units in the ROI analysis to be a beneficial method for estimating the
behavior of bioactive glasses and their healing process.
62
In eight studies97,105,109,151,166,170,171,173 biopsies of the operated site were done at
different time points when re-operated for correction of complications,
replacement of the implant due to incorrect dimensions, plate removal or during
subsequent stages of surgery like dental implant placement. Histological analysis
revealed new bone formation, the quality of new bone formation, typical reaction
layers of the bioactive glass - bone interface and resorption of the bioactive
glass.97,105,151,170,171,173 Predominantly, inflammatory changes or foreign body
reactions were not seen.151,166,170,171 On rare occasions, evidence of infection in
vitro culture166 or inflammatory infiltrate clinically109 was seen in the histological
sections but were reported to be unrelated to the bioactive glass due to its
consistent histological biocompatibilty.109 Biopsy was performed in one case with
noted complication that required a neurological procedure. The surgical site
containing hydroxyapatite onlay was biopsied.173 Intentional histomorphometric
analysis106 was performed in one study with the split mouth design.
Results of the histological study by Tadjoedin et al.,105 were given in two parts
with reports on radiological findings of the biopsied specimens prior to histological
processing and microscopic analysis. Radiology revealed areas of radiopacities
in the form of mineralized tissue at the site of reconstruction in all of the 10
biopsied patients. Light microscopy of the control sites grafted with 100%
autogenous bone from the iliac crest showed vital lamellar and some woven bone
with clearly distinguishable osteocytes and also demonstrated active bone
remodelling at 4 months post implantation. Analysis at 5 months and 6 months,
highlighted
matured
lamellar
bone
with
matured
bone
marrow
and
haematopoietic cells. One patient at 16 months showed matured dense
trabecular bone with cell-rich mature bone marrow. Histomorphometry showed
63
highest regenerated bone at 4 months and gradually decreased thereafter. A
particular trend was never traced with percentage resorption. Histological
analysis of the experimental site grafted with 50:50 of autogenous bone and
glass particles showed a different scenario compared to the control side with less
bone and more bioactive glass particles. Sections at four months revealed areas
of transformed glass granules amongst cell-rich connective tissue without any
autogenous particles visible. Evaluation at five months showed an increase in
bone volume within and around the glass particle without any connection from the
autogenous bone. The bone quality was partly lamellar and partly woven.
Histomorphometry at six months showed gradual increase in the bone volume.
The resorption pattern was noted significantly and they assumed a ‘U’ pattern.
Inflammatory cells were non-existent. At 16 months, all bioactive glass
disappeared from the experimental site with mature lamellar bone with a normal
mature bone marrow. Resorption was comparable to that of the control side.
Wide et al.,172 performed the study with the longest duration, covering a period
of 17 years from 1977 to 1994. The data of patients collected were partly
retrospective; while some of the patients were operated during the research
period. They investigated clinical outcomes of frontal sinus obliterations with
bioactive glass. All the patients were candidates with a long history of sinusitis
problem previously treated by frontal sinus obliteration. Three materials were
used for obliteration; bioactive glass, ossar and collagen matrix. Eighteen
patients out of thirty one healed well with no post-operative symptoms regardless
of the material used. Two patients were lost to review. Six re-obliterations were
performed in total due to recurrence of sinusitis or polyposis. Five of the eight
subjects who underwent filling of the frontal sinus with bioactive glass showed no
64
subjective symptoms post surgery. Only one of those subjects underwent reoperation due to local recurrence of disease at the previously operated site and
still used bioactive glass at the time of re-operation. Altogether, seven out of nine
operations showed good obliteration using bioactive glass on CT assessment.
The authors concluded that obliteration with bioactive glass is a promising option
with good post-operative results. The cosmetic complaints and major postoperative symptoms were none, except for one case of re-operation as
mentioned above which was unrelated to the material.
The longest follow-up period among all included studies mentioned was 13
years in a retrospective case series of 150 patients using a follow-up protocol of 1
week, 1, 3, 6, months and thereafter annually.106 The follow-up protocol varied
among studies, however most of the studies covered 1 month, 6 months and 12
months visit. Aitasalo and Peltola106 in their retrospective analysis of these
patients, examined the effects of bioactive glass granules in 62 patients with
frontal sinus obliteration for chronic frontal sinusitis, effects of bioactive glass
plate in 65 patients for reconstruction of fronto-orbital traumas and the effects of
bioactive glass granules and/ or plates in 23 patients for reconstruction following
fronto-orbital tumor resections. Hydroxyapatite was used in 11 patients with
extensive skull base and orbital defects caused by trauma or tumor. Fifty-nine
out of sixty-two patients with frontal sinus obliteration, 58 out of 65 patients with
fronto-orbital trauma reconstruction, 11 out of 12 patients with benign tumors and
6 out of 11 patients with malignant tumors showed good functional and aesthetic
outcomes. Three of sixty-two patients with frontal sinus occlusions were operated
again due to mucocele formation and 10 of 65 fronto-orbital trauma
reconstruction were re-operated for diplopia or enophthalmos. Hydroxyapatite
65
used for calvarial bone reconstruction in this study showed uneventful outcomes
but the results were not directly compared to that of bioactive glass. Early
complications listed for 65 trauma patients and 23 tumour patients were CSF
leak, diplopia, meningitis, oclulomotorius nerve dysfunction, ptosis and trigeminal
nerve dysfunction. Late complications were total or subtotal olfactory nerve
lesions, diplopia, mucocele, trigeminal nerve dysfunction and telecanthus.
Complications encountered in frontal sinus occlusions were mucocele in 2
patients and insufficient nasofrontal duct occlusion in one. Histological studies
paid special attention to bone and bioactive glass changes but the results were
not elaborated. The authors attributed good and reliable clinical outcomes to the
osteoconductivity and antimicrobial properties of bioactive glass already proven
by others as mentioned in the article.
4 Discussion
Reconstruction of craniofacial bone defects of different shapes, sizes and
volume are very challenging and require meticulous planning. As mentioned
earlier, the gold standard treatment modality is the use of autologous bone graft
material. Nevertheless, they carry inherent disadvantages of donor site morbidity
and inadequate supply of bone to replace huge defects. Sometimes, the shape of
autologous bone may not be a suitable option for complex shaped
reconstructions of the unique craniofacial bones. Even the best autologous
replacement may not provide aesthetically and functionally satisfactory outcomes
in the long-term because of its variable nature of volume and shape
maintenance.173 This may lead to subsequent surgeries for patch work which
66
may directly or indirectly have an impact on the psychology of the patients who
are already suffering a physically and mentally debilitating condition.
Alloplastic implants are either non-resorbable like silicone, polytel, various
polymers and titanium to specify some or resorbable such as polylactin film or
polylactide plates and bioactive glasses.177,178 Onlay structures generally used for
augmentation are autologous endochondral or membranous bone, calcium
phosphate, hydroxyapatite, wollastonite and various other composite materials.
In rehabilitation of hard tissues with biomaterials, the most essential point is an
adequate knowledge of the material, its advantages and disadvantages, its tissue
interaction and tissue toxicity and their behavior when combined with other
materials. Ideal case selection may prevent adverse outcomes. Successful
reconstruction with bone substitutes may in turn remarkably improve and
eventually increase the quality of life for the affected persons.9
Bioactive glass is characterized by osteoconductive, osteoinductive and
osteoactive responses due to its nature of absence of failure at the bone
interface.179 Pre-fabricated polymers and hard-tissue replacement polymers do
not degrade unlike the autologous bone grafts, but have shown to indulge
vascular permeation and soft-tissue in-growth after 1 week and bony in-growth
after 3 weeks.180-182 The biological factors influencing the bone graft are the type
and quality of bone concerned, its histological components, bone density, if they
are systemically compromized as in osteoporosis, periosteum condition, graft’s
embryonic origin and orientation, recipient bed conditions, location and position,
re-vascularization, graft dimension, fixation and viability, donor site conditions,
host age as well as the quality of soft tissue cover and its viability. 183-185 The
critical issue in failure of implants often attribute to the biological reactions at the
67
implant - tissue interface. Understanding the reactions of biomaterials and their
tissue response is essential for its successful implementation. Surface activity of
alloplast plays an important factor in evaluating its suitability for bone
replacement, in particular when replaced in stress bearing areas. The commonly
mentioned bone substitute complications include asymmetry, early or delayed
infection and implant dislocation or extrusion leading to eventual disintegration.
Systemic bone diseases, rheumatic diseases, metabolic disorders, allergies,
purulent bone inflammation and insufficient soft tissue coverage pose as deciding
factors for the elimination in case selection and choice of treatment modality of
alloplastic reconstruction for successful outcomes.9 In spite of a sensitive
scenario, there has been a considerable increase in the use of biomaterials in the
last 10 years as they provide an attractive alternative, having potential
advantages of limitless supply of stock and absence of morbidity to the
donor.138,173 The ease of material use, its unlimited off-the-rack availability along
with long shelf-life, its biocompatibility in situ, and its purpose to reduce the
operating time make them increasingly in demand.138,173
Biomaterials have been used historically and have rapidly progressed in other
surgical specialties. They are more often used for the repair of long bone defects
and spinal fusion by orthopedic surgeons and neurosurgeons likely. They have
found its use in other specialties like ENT as well. Unfortunately, plastic surgeons
have approached the use of biomaterials in the craniofacial skeleton with
ambiguity and poor outcome of a specific biomaterial in a single application is
usually generalized to all other materials in the black box regardless of their
purpose.173 Hence, bioactive glass which gained popularity in the early years of
its discovery was sidelined and became a rare occurrence later.
68
Exercising biomaterial use is currently not well defined with operator preference
often the disposing factor and especially bioactive glass has been slow and at a
certain point stagnant to gain popularity as there is little or no information
regarding systematic guidelines as to which biomaterial to use for specific clinical
scenario.173 Bioactive glass, the material of our interest shows promising qualities
consistently. Besides being proven with numerous in vitro and animal studies to
be osteoconductive, they also recruited osteoblasts from the adjacent bone for
replacement over time, which characterized by the absence of breakdown at the
bone interface proved to be an osteoactive or osteoproductive material as well.
Orbital Wall Reconstruction
The most frequent damaged structure of the maxillofacial skeleton in facial
trauma is the orbital floor. In addition, maxillary or fronto-orbital tumors warrant
orbital wall reconstruction. Unfavorable outcomes are frequent with orbital floor
reconstruction due to the difficulty in restoring its esthetics and function
symmetrically owing to the intricacy of its anatomy. The main aim of
reconstruction would be to restore the eye as near to it pre-operative position as
possible, which involves repositioning herniated orbital tissues and repairing the
defect that caused its deformation. At the same time, they prove beneficial in
overcoming if not all but some of the symptoms like diplopia, infra-orbital nerve
damage, exophthalmos or enophthalmos without any radiographic evidence of
herniation of orbital fat into the antrum.174 The key to satisfactory final outcome is
to preserve the orbital volume. The main challenge in using bioactive glass plates
in orbital reconstruction is selecting the proper size and shape compatible with
the bone defect.97,174 Repair of orbital floor fractures with bioactive glasses
69
demonstrated successful outcomes174 with appreciable maintenance of globe
position in follow-up of up to 1 year.174,186 They also did not appear to have any
toxic effect on vital structures like the optic nerve or infra-orbital nerve in close
proximity to the reconstructed site.174 Extrusion of implant was reported in 20
percent of the cases requiring another surgery to re-shape and reduce the
implant size for adequate soft tissue cover.174 Peltola et al.,97 presented a
satisfactory clinical outcome at the end of two years with an overall complication
rate of 9 percent using bioactive glass plates in the reconstruction of orbital bony
wall defects. The majority of the complication was unrelated to the implant itself,
except where an inappropriate size of the implant chosen by the operator led to
its complications. All well-fitted glass plates most often did not require any
additive fixation method like placement of screws174 either resorbable or nonresorbable. The use of metal templates for appropriate choice of bioactive glass
plate during planning or intra-operatively has enhanced its accuracy.106 The
bioactive glass meets most of the criteria for a beneficial orbital wall
reconstruction material. It could most probably be claimed as the only
antibacterial orbital reconstruction material through its well proven antimicrobial
activity described in the literature.150-156 Although the study did not measure
specific parameters to confirm its antimicrobial effect and its rate of degradation 2
years post-operatively, it is understood that a good clinical outcome with no postoperative infections is most likely due to both the osteoconductivity and the
antimicrobial or bacteriostatic174 properties of bioactive glass. Laboratory studies
did not highlight any inflammatory parameters or impaired liver and/ or kidney
function.97,174 To summarize, bioactive glass yielded positive and predictable
70
clinical results with a certain degree of ease to handle the material prior or at the
time of reconstructive surgery.
Frontal Sinus Obliteration
Frontal sinus obliteration with autogenous fat has showed variable success with
failure rates ranging from 3 percent to 25 percent as reported by Bergara and
Itoiz187; Montgomery and Pierce188 and subsequently by others.189,190 Autogenous
obliteration has been avoided mainly to skip any second procedure for graft
harvest and consequently to avoid post-operative morbidity.171 Favorable
outcomes with acrylate and proplast was demonstrated by Failla 191 and Barton192
respectively. Other materials reported in the literature for the same purpose were
bovine bone granules, biochoral and ceramic hydroxyapatite.193-195 Peltola and
associates196 reported the use of bioactive glass particles to fill frontal sinuses in
30 patients over a 10-year period. Although radiologic density was reduced,
bioactive glass particles still retained their volume and were well tolerated by the
patients. Peltola et al., 2006151 in their study showed favorable results with total
complication rate of 7.2 percent which was still lower than previously
reported190,197 cases. The indications for re-obliterations were probably not due to
inadequate operative technique and not related to the properties of bioactive
glass. An important aspect to be noted here is that the osteogenesis in
periosteum- and endosteum-free frontal sinus of the obliterated frontal sinus may
assumably occur as a result of metaplasia of connective tissue rather than the
osteoblastic theory.198 Animal study199 on rabbit has proven beneficial and faster
healing with free periosteal flap in the region and the healing and revascularization of the periosteum greatly influences the bone formation. There
71
was consistent decrease in the Hounsfield units starting from 1 week to 48
months with average density reduction of 7.1% from 1 week to 6 months, 14.5%
at 1 year and thereafter 20% up to 24 months.166 Reliable estimation of BAG
obliteration was made with the ROI method.166,196,200 Other means successfully
demonstrating the growth of bone, fibrous tissue and the amount of bioactive
glass or hydroxyapatite in experimental study was three different staining
methods namely Haematoxylin and Eosin, Toluidine Blue and modified van
Gieson; Toluidine blue being better than the rest.199 Dissolution of silicon and
phosphorous from the BAG granules influenced the decrease of Hounsfield units
in the ROI evaluation.151,166 Promising outcomes in terms of antibacterial
properties both experimentally and clinically155 was displayed.151,166 Antibacterial
properties of BAG under experimental conditions exhibited excellence 157,159,196
and hence in principle may provide favorable results under clinical setting. Yet,
the antibacterial property in chronic frontal sinusitis patients needs further
research.151 In the study by Aitasalo and Peltola,106 the patients on whom several
frontal sinus operations had been performed previously before the bioactive glass
obliteration had suffered longer periods of post-operative discomfort compared to
those patients with fewer previous operations. The long term complications
reported were mucoceles in two patients and insufficient obliteration due to
incomplete naso-frontal duct occlusions. The overall complication rate in frontal
sinus surgery was 7.2 percent, lower than previously described according to
these authors. Other post-operative complications reported in the literature were
neuralgia and paresthesia of the frontal region. But they were unrelated to the
bioactive glass material used. The investigators attributed this complication of
probable damage to the supra-orbital and supra-trochlear nerves due to the
72
eyebrow incision from the previous scar. Other reason may be due to the nature
of the previous surgery performed on these patients which in the first place could
have induced the neurological symptoms. Re-infection necessitating re-operation
with subsequent symptomless healing was seen in a case of an earlier
trephination hole, which actually supports the fact that the material may not be
the reason for cause of infection rather a pre-existing condition or inadequacy of
the operation. Besides these, the overall esthetic outcome was satisfactory.171 An
important point to be noted from the literature by Wide et al., 1997172 was that
even though the results were excellent with bioactive glass, one patient required
re-operation for frontal sinus obliteration. They would like to highlight the cause of
recurrence of the disease to a very aggressive form of sinus infection.
Evolutionally, the frontal sinus is a form of ethmoid cells even though they are
anatomically separate.201 Hence, as surgeons an appropriate surgical plan to
concomitantly treat related sinus cavities associated with the frontal sinus or the
cause of chronic infection for a successful outcome is warranted. Even if proven
that bioactive glass did not encourage bacterial growth, 150-156 it is beyond the
scope of the material to treat infections in its chronicity whether related or
unrelated to its anatomical location. Therefore, for success in frontal sinus
obliteration, treating the infection with various measures and at the same time
sufficient obliteration may reduce adverse outcomes. It is felt that, the main
drawbacks of insufficient obliteration or infection of the sinus cavity in fact can
only be improved with the surgeon’s expertise and judgment for ideal case
selection rather than improvising on the material itself.
73
Cyst/ Tumor Rehabilitation
Rehabilitation of the dental arch with a fixed prosthesis can be compromized by
pathological manifestations like cyst and tumors. They not only affect the
prognosis of the abutment teeth but also jeopardize the esthetics and the
adaptation
of
the
fixed
prosthesis
to
the
residual
alveolar
ridges. 202
Hydroxyapatite is often attempted to fill bone cavities with subsequent new bone
formation along the surface of the material. Allografts and xenografts are
associated with its own inherent risks of disease transmission and poor
biocompatibility if case selection and appropriate indications are not instituted.
Schepers et al., 1991203 compared narrow range bioactive glass particles with
hydroxyapatite and found greater osteoconductive response around the glass
particles. Though hydroxyapatite has provided enhanced bone tissue repair, their
results are inconsistent. They also noted that glasses with a specific narrow size
range allow for preferential resorption which is not seen otherwise. Granules of
uniform dimensions allow room for empty spaces between them which may allow
tissue infiltration and regeneration. With a wider size range, the smaller particles
fill up the spaces between the larger ones. Failures were noted in defect spaces
of apical root resection filled with bioactive glass. In some cases infections
recurred and the glass particles used were noted to be fibrously encapsulated
and comparable to the results of hydroxyapatite or porous ionomer.204,205
Schepers et al., 199399 reported one in sixteen cystic defects re-infected, but the
probable cause was unrelated to the bioactive glass particle used but rather to
the persistent fistula associated with it prior to surgery. Six out of the eight teeth
with supposedly unsalvageable perio- or endo- related problems, survived
rehabilitation with glass particles. El-Ghannam et al., 2004147 demonstrated graft
74
material resorption in maxillary cystic bone defects with decreased bone density
that indicated faster cell-mediated material resorption versus accelerated bone
tissue regeneration. In total, bioactive glasses seems to be beneficial for
rehabilitating the cystic defects with small drawbacks like infection which can be
overcome with meticulously planning and execution of eliminating the pathology
and treating the necessary case with post-operative antibiotics as a prophylactic
measure to prevent infection.
Periodontal
Rehabilitation,
Extraction
Socket
and
Alveolar
Ridge
Restoration
Long term results of bioactive glass and demineralized freeze dried bone
allograft were comparable in periodontal defects with moderate to deep
pockets.40 Similar agreeable results were demonstrated in new extraction sockets
filled with bioactive glass.206 Authors showed promising results for bioactive glass
used in conjunction with polytetrafluoroethylene barriers in periodontal defects. 207
However, other studies exhibited equivocal new bone regeneration when
bioactive glasses were used solo in periodontal defects and for alveolar ridge
augmentation.109,168 Besides bone regeneration they also helped in the
restoration of the gingival attachment following third molar extractions 168 and for
the prolonged survival of dental implants placed in augmented areas.109
Minimal bone was formed in the healing socket post tooth extraction
accompanied by increased resorption of alveolar ridge at the same time.208 If this
occurs in individuals older than 25 years, an osseous defect may persist as a
result of periodontal breakdown posterior to the second molar with loss of
supporting structures distal to the second molars after third molar surgery.209
75
Augmentation procedures are done mainly to preserve the alveolar ridge height
and at the same time to maintain the buccal wall contour. Delayed bone
augmentation is done to allow and gauge the bone regeneration within the
extracted socket and to attain optimal soft tissue regeneration for adequate cover
post-augmentation. Simultaneous augmentation of the extracted tooth socket is
done chiefly to maintain the ridge form and concurrently provide stability and
retention of immediate implants, promote periodontal health and present
conditions for a good prosthetic rehabilitation.168 The most common autogenous
bone grafts to augment these alveolar ridge defects are the iliac crest and rib
from distant sites, although tibial bone has also been used in some cases; ramus
bone, symphyseal bone and bone from the maxillary tuberosities or tori within the
intra-oral sites. Allogenic bone grafts like tricalcium phosphate and porous
hydroxyapatite were most commonly used. Adequate blood supply, inconsistent
performance, inability to restore the full alveolar ridge height, prolonged healing
period and potential transmission of adventitious agents were the limiting factors
for using various other options. Correction of osseous defects is often attempted
with calcium phosphate ceramic particles. However, they act as filler materials
and any new bone formation takes place only along its surface.168
Dense and porous hydroxyapatite and tricalcium phosphate particulates have
also been in common use as filler materials providing a favorable setting for
enhanced bone repair and growth.168 Bio-Oss® reportedly a xenograft of
anorganic bovine hydroxyapatite origin is supposedly resorbable, however
recently proven to be unpredictable in terms of new bone formation and material
resorption.210,211 Successful treatment of ridge augmentations, extraction sites
and
periodontal
osseous
defects
were
76
accomplished
with
bioactive
glasses.40,212,213 With increasing awareness of dental implants, more patients are
opting for it over conventional alternatives. As a result of the increase in demands
from patients, many less-than-ideal sites need prior bone augmentation before
implant placement. A statistically significant increase in the attachment level was
calculated by Throndson et al., 2002168 from baseline to post-operative 3 months
when grafted with BioGran®, which is a commercially available bioactive glass,
whereas their controls of un-grafted sites showed a loss in attachment level.
There was no significant effect of time and also no significant changes in the
radiographic measures between grafted and un-grafted sites over a period of
time. Bioactive glass is considered easy to handle due to its hydrophyllic nature
allowing it to absorb surrounding tissue fluid making it easily moldable and
placeable at surgical sites. Membranes may or may not be used for security
cover but its beneficial effects are unknown. Also its individual effects and
variable outcomes may influence the outcome of test material. Although some
wound dehiscence were noted with superficial loss of the bioactive glass in the
first post-operative week, the loss was minimal and resolved during the second
week. Less pain was noted post-operatively in the grafted versus the un-grafted
site. Some patients developed localized osteitis as a complication of non-grafted
alveolar sockets but none on the grafted sites. There was overall decrease in the
clinical attachment level and loss of alveolar bone height at the end of one year in
both the experimental and the control sites but more on the control sites. The
authors briefed that bioactive glass was biocompatible and biologically well
accepted with minor complications of wound dehiscence solved by granulation by
secondary intention soon after. Although a routine use of bioactive glass in third
molar extraction sites and in older patients may not be suggested, they still prove
77
beneficial in deep impacted teeth with substantial loss of alveolar bone and those
posing risks for increased periodontal pockets.168 Re-intervention by adding glass
particles in exposed extraction sockets due to lack of adequate soft tissue cover
resulted in excellent clinical picture in the study by Schepers et al., 1993.99 They
also noted changes in the vertical dimension, whereas nearly no changes in the
horizontal direction for the correction of defective alveolar ridges. This was seen
only during the early phase at around 2 months time and stabilized after 3
months. No additional changes were registered after rehabilitation with fixed
prosthesis.99 Camargo et al., 2000214 showed positive results with the use of
bioactive glass in conjunction with calcium sulfate in the extraction sites. In the
study by Norton et al., 2002109 he submitted mixed results post implant placement
in the extraction sites grafted with two types of commercially available bioactive
glass either with or without a membrane placement. Failure due to severe pain
associated with osteotomy preparation in two patients out of seventeen, in whom
the pain was uncharacteristic of dental implant placement and unremitted was
removed only two to three weeks later to resolve the pain. Three of the four
implants did not survive post dental implant placement in a patient who was
subsequently diagnosed with colon cancer. Although the author proposed an
immuno-compromized status of the patient for the failure of implants, it may not
be the sole reason and it also raises the doubt whether it was a systemic problem
or if local factors were involved. In addition, three membranes became exposed,
necessitating their early removal in two patients because of infection. This
created a negative impact on the outcome of the graft as well. Histological
sections exposed mixed responses. Glass was intimately related to an adherent
connective tissue. There was evidence of an inflammatory infiltrate in specimens
78
from one of the patients but it was considered to be more likely due to the
inflamed periodontal tissue and not as a response to the glass itself, since there
were no macrophages. There was absence of new bone in the core biopsies
taken within 6 months and was seen only later. They were of mixed woven and
lamellar character, noted at the periphery and centrally within the biopsied
specimens suggesting new bone growth by apposition underscoring its
osteoconductive and osteoproductive properties. It was also possible to
demonstrate bone formation within the central cavities of the individual glass
particles. Characteristic fissuring of the glass particles was routinely seen in all
specimens under light microscope, but the histopathologist was unable to
determine the difference between BioGran® and Perioglas® that was used. The
authors have thoroughly thought about the results being biased with the use of a
single batch of these graft materials but ascertained with the manufacturer that
no such influence is possible. The healing period varied from 3 to 11 months and
was confirmed with clinical and radiological parameters. The final clinical
outcome was a 48 percent true success with no marginal bone loss, while 52
percent showed some bone loss in the range of 0.7 to 2.2 mm, but not even one
approaching the levels over one-thirds of the implant height. The cumulative
success rate was 90%. If the patient with colon carcinoma was excluded, the
cumulative success was regarded as 96.8 %. A success rate with histological
evidence was difficult and especially in humans because majority of the studies
using bioactive glass have expounded its success by clinical rather than
histological means,40,215-217 which is not always feasible in all situations. The twostaged technique gives scope for re-entry not just for biopsy but at the same time
placement of implants. The study by Nevins and associates218 was the first to
79
provide a series of cases with histology for patients treated with Perioglas® for
repairing periodontal defects. Success rates not only demand for the restoration
of bone structure by augmentation but also the regeneration of periodontal
ligament, cementum and the host bone itself wherever applicable.168 Even though
the researchers mentioned that the earlier placement of implants into the grafted
site did not negatively influence the clinical outcome with respect to implant
success, they still had a limitation of using single implant system instead of
different designs, which may or may not have influenced the stability of these
implants.
Sinus Floor Augmentation
A composite mixture of 80-90 percent bioactive glass particles and 10-20
percent autogenous iliac bone was compared to 100 percent autogenous iliac
bone in sinus floor augmentation219 and was found by histomorphometric analysis
that bioactive glasses accelerated healing and bone regeneration in 6 months,
compared to 12 months in autogenous bone alone. Tadjoedin et al., 2000105 used
1:1 ratio of bioactive glass and autogenous bone for sinus elevation and
displayed results under various parameters of bone turnover like osteoid
percentage, percentage of resorption surface and mineral apposition rate
percentage as measured by tetracycline labeling. Histological analysis at different
time points supported the findings. All bioactive glass particles had vanished by
resorption at 16 months post-augmentation and had been replaced by bone
tissue starting from 4 months. Accelerated bone regeneration means the ability
for simultaneous dental implant placement and was successfully demonstrated
by Cordioli et al., 2001170 with a 4:1 ratio of bioactive glass and autogenous bone.
80
He noticed an increase in mean mineralized tissue height of 7.1 mm during
second-stage implant surgery. As opposed to other studies, a healing period of
9–12 months was maintained instead of 6 months or less because of the
persistent presence of osteoid bands in the biopsy cores which indicated ongoing
bone formation still under process after a healing period of 9–12 months. The
success of the treatment in sinus floor augmentation mainly relies on the
appropriate case selection. He carefully excluded the inappropriate patients like
smokers, patients having systemic contraindications to oral surgical procedures
or implant therapy, those with recent extractions in the graft site less than a year,
patients presenting with thin alveolar ridges which may not allow primary stability
and those with ongoing or pre-existing maxillary sinus pathology.170 They were
the most crucial predisposing risk factors for the success of bone augmentation
and implants at the maxillary sinus region having less than 5 mm of crestal bone
height in the posterior maxilla. The beneficial combination of BioGran® and
autogenous bone was demonstrated with stable and predictable results for
implant success. This study elaborated that the osteogenic potential in the form
of bone morphogenic protein and host growth factors to produce osteoinductive
properties along with the osteoconductive and osteoproductive properties of
bioactive glass gave successful results graded by the criteria according to
Albrektsson et al., 1986.220 Osteoprogenitor cells re-populating the grafts were
mainly derived from the residual maxillary alveolar ridge and not from the sinus
membrane which was lacking any osteogenic potential.170 Histological sections
stained with Goldner’s trichome method for light microscopy stained light green
indicative of mineralized tissue and connective tissue. However, the particles of
bioactive
granules
were
recognizable
81
despite
this
transformation.
Histomorphometry at 4 months revealed 41 percent of bone tissue, with only a
slight increase to 45 percent at 12 months time. At 16 months, the value of bone
tissue grafted with 1:1 ratio of bioactive glass and autogenous bone showed
higher percentage of bone tissue compared to its control grafted with only
autogenous bone. The percentage resorption was not significant and did not
show a particular trend with values fluctuated between 4 percent and 10 percent.
The resorption pattern assumed a U-form with one wall of the implant completely
resorbed and the bone being mostly of lamellar type devoid of inflammatory cells.
Histomorphometry also displayed clear bone augmenting capacity of bioactive
glass particles ranging from 300 – 355 μm and pointed out that co-transplantation
of autogenous bone may not be necessary for sinus floor augmentation.
However, further studies for minimizing the amount of bone graft are imperative
before clinical recommendations can be made. The quality of bone at the
experimental and control sites suggested that lamellar bone at the sites grafted
with autogenous bone alone found lamellar type bone as early as 4 months
whereas those with composite bioactive glass and autogenous bone had lamellar
bone only later at 6 months. Notably at 16 months, there was no significant
difference in quality and density of bone at both sites. Interestingly the density of
new bone at the grafted sinus was more than the harvested iliac site. The
bioactive glass started to resorb from 4 months time after the operation, while
new bone formation around it occurred without any apparent biological response
or mutlinuclear giant cells as seen when other bone substitutes were used. 105
82
Craniofacial bone reconstruction
Literature presents with various options in the reconstruction of defects of the
facial bones. Besides the evergreen autologous graft, various alloplastic
materials have also demonstrated good outcomes. Methyl methacrylate, silicone
rubber, polyamide and polytetrafluoroethylene have all been used. 221-225 They
remain intact and do not resorb but depend mostly on fibrous union to stabilize
them in place through encapsulation or in-growth into a porous structure.
Biocompatibility of calcium phosphate ceramics, bioactive glasses and glassceramics as potential reconstructive materials have been displayed by a
chemical bond to living tissue on various tests like scanning electron microscopy,
energy dispersive radiographic studies and push-out tests. A controversy still
exists for the surgical reconstruction of anterior skull base lesions and treatment
of fronto-orbital chronic infection.106 Calvarial bone defects with full thickness
reconstruction employing bioactive glass particles in pediatric patients were
successfully demonstrated with recall CT scans that showed the material
transformation to regenerated bone from the host with substantial density in 6
months time. There was no need for re-operation or biopsy of the implanted
material due to nil adverse outcomes.226
In experimental studies,144,146 bioactive glass produced more new bone
compared to hydroxyapatite and tricalcium phosphate materials. Unsatisfactory
long term results were seen with hydroxyapatite cements because of delayed
inflammatory responses, exposure of the material and the relative risk of
infections originating from the frontal sinus area.227,228 On the contrary, the study
by Aitasalo and Peltola, 2007106 used hydroxyapatite in defective calvarial bone
reconstruction
with
uneventful
consequences.
83
However,
controversial
conclusions concerning the use of hydroxyapatite in the head and neck
reconstructions have been presented by some others.227,229,230 Autoclaved
autogenic bone and PMMA still showed higher infection rate in delayed
cranioplasties compared to titanium mesh.231 But surprisingly, reconstruction of
large skull bone defects with composite BAG and PMMA showed no long-term
complications such as implant-induced skull resorption, loosening of implant or
late infections. Their esthetic and functional outcomes were commendable. The
researchers
concluded
that
irritation
reactions
caused
by
exothermic
polymerization of PMMA and the presence of free and residual PMMA monomers
before and after polymerization can be minimized by controlling the implant
manufacture conditions prior to surgery. They also highlighted that even though
the cost of bioactive glass materials may be expensive, their use serve to reduce
the operating time, hospital stay, and in turn treatment costs; and at the same
time reduce the patient morbidity. The intra-operative handling of these materials
were easy and was possible to add or re-modify their shape with ease in cases of
unanticipated extent of hard tissue defect or soft tissue defect for complete
coverage of the implant material.170 Similarly, autogenic bone is still considered
advantageous
by
some
because
of
its
satisfactory
long-term
clinical
experience232,233 and also because of its re-shaping properties being better106
than bioactive glass or hydroxyapatite. The mechanical and compressive strength
is lower in cancellous bone but higher in cortical bone compared to bioactive
glass.5,234,235 Bioactive glass is rigid and brittle with low fracture toughness and is
mechanically weak5 and considered unsuitable106 for areas that are load bearing
and where re-shaping of the material is mandatory. But with advances in
technology
with
stereo
models
and
84
computer
assisted
fabrication
of
reconstructive scaffolds, manufacturers cum clinicians will be able to overcome
this setback.
Craniofacial reconstruction dictates a specific and unique set of requirements in
pediatric patients because; the continued growth of the craniofacial skeleton is
viewed as a fourth dimension in formulating the final reconstruction. Bioactive
glass particles were used for inlay reconstruction of a residual cranial vault defect
in a child who had left unicoronal synostosis and underwent fronto-orbital
advancement along with cranial vault remodeling at the age of three. Bioactive
glass supported by a resorbable plate was placed on the endocranial surface for
inlay
augmentation.
Post-operative
computed
tomography
demonstrated
significant mineralization of the residual defect to approximate the adjacent native
calvaria a year later. No lingering irregularities of bone or other complications
were reported. All cranial defects reconstructed had a maximum width of 5 cm or
less in all patients reconstructed with bioactive glass. Demineralized bone matrix
is an alternative for inlay calvarial reconstruction with comparable results to
bioactive glass and some of the defect size were greater than 5 cm. The followup CT scan at 1 year showed inadequate mineralization at the periphery of the
defect in a fronto-parietal reconstruction requiring second surgery to correct it.
Comparable results of inadequate bone mineralization were seen in a parietal
defect correction with demineralized bone struts. Pre-fabricated polymers used in
six children for facial reconstruction like malar augmentation, inlay calvarial
reconstruction on post-operative CT scans showed bone density that never coordinated with the surrounding facial skeleton or calvaria. Moreover, one patient
developed peri-implant infection needing drainage, serial irrigations and intravenous antibiotics to resolve it.173 Clinical experience has consistently proven
85
significant resorption of autogenous bone graft when used as onlay for facial
augmentation.236 Complete resorption of an onlay in sheep model was noted one
year post-operatively but these findings are non-comparable to humans. In
contrast, hydroxyapatite derivatives were tested in both onlay and inlay settings
and found to maintain its volume and are significantly replaced by bone in one
year. Especially in growing children, the craniofacial bone remodeling is
unpredictable compared to adult counterparts and required second or a series of
surgeries for corrections mainly for esthetic reasons. Biomaterials have been
beneficial in such patients and precisely materials with osteogenic potential have
helped in scenarios where the osteogenic potential of the craniofacial skeleton
itself is reduced.173
Complication of a large hematoma in a single patient was reported by Dušková
et al., in 2002.9 Extrusion was observed in 20.45% cases mainly related to less
than optimal soft tissue quality like scars and congenital hypoplasia in patients
with clefts and a case of irradiated maxilla after maxillectomy. A combination of
post-operative scarring, congenital hypoplastic soft tissue and contemporary
fistula were the cause. After two unsuccessful attempts in a patient with complete
left cleft with a wide oronasal fistula, the implant was removed due to failed
treatments to resolve the problem. There is an anticipated slow metabolism in
clefts and irradiated bone, therefore a less growth ability in affected areas
showing a rise of connective tissue faster than the chemical bond inception was
affirmed. The median time of extrusion of implants was five months and no real
bond was found between the implant and the bone tissue in those cases, only a
fibrous capsule was found. Experimental techniques of energy dispersive
spectroscopy,
wavelength
dispersive
86
spectroscopy,
x-ray
dispersive
spectroscopy and micro hardness measurement were used to study the implant
tissue changes. The most important positive outcome noted was nil fracture or
shape instability of these bioactive glass ceramic implants during clinical
observation. Also, there was no degradation or pathologic reaction in the
adjacent tissue.
Elshahat, 2006167 in his study showcased classical midface and nasal
deformities due to congenital, post-surgical and traumatic defects corrected by
reconstructive surgery with bioactive glass. The overall success rate and clinical
outcome with patient satisfaction was tremendous with only two cases of material
extrusion on the immediate post-operative day which stopped spontaneously
without any adverse outcome.
Sometimes it is difficult to recall a well recovered, fully satisfied patient with
facial bone defects. That is how even if there were 13 patients at the beginning of
the study, only six of them were reviewed over a year. Suominen and
Kinnunen175 showed that bioactive glass presented satisfactory results in a
variety of facial bone defects. The unsatisfactory outcome was more attributed to
the surgical technique, inaccuracy of placement of implants, infection unrelated to
the bioactive glass implant or mucocele formation, which once treated resolved
with no further problems. Authors observed resorption of 40 percent of the grafts
at the rate of 25-50% for autogenous bone as opposed to 14 percent for fixed
onlay and 45 percent for unfixed grafts in sheep. 237 Iliac bone grafts in the floor of
the orbits are subject to 33 percent resorption in monkeys. 238 However this is not
a valid comparison because of difference in species and their physiology is not
the same. There is variable resorption noted between glass granules and plates
and among the different sites which makes it difficult to gauge the resorption
87
rates based on its molecular structure and the anatomical site. In a solid block
form it does not resorb and gets incorporated into bone quite well. The contact
areas also appear differently with different forms of glasses over a period of time
which makes it difficult to get an accurate time period for conversion of these so
called glass particles into host bone or host-like bone. However, Suominen and
Kinnunen175 provided results for glass plate incorporation to be better than bone
grafts and glass granules in their study. They have also made recommendations
that reaction behaviors in bioactive glasses can be regulated by modifying their
chemical composition as proven in various experimental studies whereas the
opportunities for adjusting the biological properties of hydroxyapatite are more
limited. Almost unanimously, all authors give the impression of bioactive glass to
be resistant to infection, which is either proven clinically in the absence of signs
of infection or microbiologically through histological specimens showing nil
bacterial growth. The heterogenecity of the sites and the unique nature of each of
the facial bones either single or paired most often make it difficult for statistical
analysis but may still allow some semi-quantitative and qualitative conclusions
like our evidence based review.175
5 Conclusion
It is a pity that biomaterials are condemned by many surgeons without critical
analysis of their circumstantial use. An ideal implant material must be biologically
compatible, non-carcinogenic, non-allergic, appropriately resorption resistant,
deformation resistant, easily fixed to host tissue, yet easily removable,
sterilizable, and resistant to microbial infiltration, easily adaptable, moldable and
re-shapeable,
radiologically
visible,
88
low
in
thermoconductivity
and
electroconductivity. Many still seek help after exhaustive treatment. They may not
be convinced for another extensive and complicated operation, but they still
cannot accept their current appearance. An ideal solution for such patients is
bioactive bone substitutes.9 But basic surgical experience, operator skill and
precision of planning are still significant factors for success.106 However, it is still
considered limited literature and clinical experience for extensive facial skeleton
augmentation with bioactive glass over other pre-fabricated implants.138
It is
therefore necessary to develop an evidence based biomaterial specific guide line
and algorithm similar to that given by Gosain et al., 2009173 only more
comprehensively. A protocol for bioactive glass may prove useful in choosing this
material for craniofacial reconstruction.
The future of these brilliant bioactive materials can be seen in tissue
engineering. They unite functionally adaptive bone from recombinant osteogenin
with related bone morphogenetic proteins, collagenous matrix, and responding
cells with the possibility of creating and shaping a new artificial bone that is
compatible with natural biomechanical function. These revolutionary changes
may allow intrauterine surgical intervention or even genetic engineering in
congenital cases.113,239-244
89
Annexes
FIGURES AND TABLES:
A: Bone Bonding
B: Non-bonding (reactivity too low)
C: Non-bonding (reactivity too high)
D: Non-bonding (no glass formation)
SiO2
S: Soft-tissue bonding
E: Bioglass® composition
A-W Glass-ceramic
(variable P2O5)
CaO
Na2O
6% P2O5
Figure 1. Diagrammatic representation of the compositional dependence of
bone-bonding activity in bioactive glasses and glass-ceramics. Note regions A,
B, C, D and S displaying varying degrees of bioactivity. (Extracted17 and
modified)
90
Tissue Related
Implant Related
Type of tissue
Implant composition
Health of tissue
Phases of implants adaptation
Age of tissue
Reactivity boundary of implants
Circulation within tissue
Dimension and surface reactivity
Circulation at the interface
Porosity and inter implant reaction
Mobility at interface
Chemical and biological bond
Adaptation of tissue to implant
Integration of implant to tissue
Loading
Response to loading
Table 1. Factors potentially affecting the implant - tissue interface response.
Material Property
Tissue Response
Toxic
Surrounding tissue dies
Bio inert
Fibrous tissue of variable thickness forms
Bioactive
Interfacial bond forms
Biodegradable
Replaced by surrounding tissue
Table 2. Properties of materials and their corresponding tissue response.
91
Product
Composition in mole percentage (mol. %)
45S5
46.1 SiO2, 26.9 CaO, 24.4 Na2O and 2.5 P2O5
58S
60 SiO2, 36 CaO and 4 P2O5
S70C30
70 SiO2, 30 CaO
Schott 8625
Fe2O3 based IR absorbing biocompatible implantable transbonder
Table 3. Food and Drug Administration (FDA) approved bioactive, biocompatible
glass and its composition.245
92
MATERIALS
42S5.6
46S5.2
49S4.9
52S4.6
55S4.3
60S3.8
45S5
45S5F
45S5.4F 40S5B5 52S4.6
55S4.3
8625
KGC
KGS
KGy213 Bioactive Nonbioactive
Bioglass Bioglass Bioglass Bioglass Bioglass Bioglass Bioglass Bioglass Bioglass Bioglass Bioglass Bioglass Schott
Ceravital Cervital Ceravital Ceravital Ceravital
Si02
42.1
46.1
49.1
52.1
55.1
60.1
45.0
45.0
45.0
40.0
52.0
55.0
46.2
P2O5
2.6
2.6
2.6
2.6
2.6
2.6
6.0
6.0
6.0
6.0
6.0
6.0
CaO
29.0
26.9
25.3
23.8
22.2
19.6
24.5
12.25
14.7
24.5
21.0
19.5
Ca(PO3)2
CaF2
12.25
46.0
38.0
20.2
33.0
31.0
25.5
16.0
13.5
A-W GC MB GC
40 – 50
30 – 35
34.2
19-52
10 – 15
7.5 – 12
16.3
4-24
30 – 35
25 - 30
44.9
9-3
9.8
0.5
MgO
2.9
2.5 - 5
1 – 2.5
5 - 10
3.5 – 7.5
3-5
0.5 - 3
0.5 - 2
3-5
4.6
5-15
MgF2
Na2O
26.3
24.4
23.8
21.5
20.1
17.7
24.5
24.5
24.5
24.5
21.0
19.5
4.8
K2O
5.0
4.0
0.4
Al2O3
B2O3
7.0
5-15
6.5
5 – 15/ 1 - 5
12-33
5.0
Ta2O5/TiO2
Fe2O3
STRUCTURE Glass
Glass
Glass
Glass
Glass
Glass
Glass
Glass
Glass
Glass
Glass
Glass
Glass
Glassceramic
Glass- Glassceramic ceramic
Glassceramic
Glassceramic
Glassceramic
Glassceramic
REFERENCE 246
246
246
246
246
246
18
18
18
18
18
18
245
85
85
246
246
86
247
Table 4. Bioactive glass and glass-ceramics in experimental clinical use
(Extracted42,245 and modified)
93
42
LIST OF ABBREVIATIONS
1.
HA - Hydroxyapatite (a.k.a., hydroxylapatite)
2.
T0.5bb - Time needed for 50% of the interface to bond to bone
3.
IB - Bioactivity index
4.
P2O5 -Phosphorus pentoxide
5.
Na2O – Sodium oxide
6.
HCA - Hydroxy carbonate apatite
7.
FA - Fluoroapatite
8.
V2O5.P2O5 – Vanadium phosphate
9.
Sio2 – Silicon dioxide (a.k.a., silica)
10.
CaO – Calcium oxide
11.
wt. % - Weight percentage
12.
Al3+ - Aluminum ion
13.
Ti4+ - Titanium ion
14.
Ta5+ - Tantalum ion
15.
B2O3 - Boron trioxide
16.
CaF2 – Calcium fluoride
17.
SBF – Simulated body fluid
18.
MgO – Magnesium oxide
19.
Fe2O3 – Ferric oxide
20.
F- - Fluorine ion
21.
m2/ g – Square meter per gram
22.
Y2O3 – Yttrium trioxide (a.k.a., yttria)
23.
Al2O3 – Aluminum trioxide
24.
KG Cera – KOMAGE Gellner ceramics
94
25.
A-W.GC – Apatite-wollastonite containing glass-ceramic
26.
A.GC – Apatite glass-ceramic
27.
A-W-CP.GC – Apatite-wollastonite calcium phosphate glass-ceramic
28.
A-W-(Al) – Non-bioactive alumina-containing glass-ceramic apatitewollastonite
29.
Si-OH – Silanol group
30.
G13 – A type of glass
31.
GC13 – A type of non-bioactive ceramic
32.
HCl – Hydrochloric acid
33.
SEM - Scanning electron microscopy
34.
FTIR - Fourier transform infrared reflection
35.
Si4+ - Silicon ion
36.
P5+ - Phosphorus ion
37.
Na+ - Sodium ion
38.
Ca2+ - Calcium ion
39.
XPS - X-ray photoelectron spectroscopy
40.
IR - Infrared spectroscopy
41.
AFM - Atomic force microscopy
42.
SBF-K9 – A type of simulated body fluid
43.
EDX - Energy dispersive x-ray
44.
LiFe5O8 – Lithium ferrite
45.
Fe3O8 – Magnetite
46.
XRD - X-ray diffraction
47.
1-98 bioactive glass – A type of bioactive glass fiber
48.
TiO2 – Titanium dioxide
95
49.
K – ° Kelvin
50.
Ca2P2O7 – Calcium pyrophosphate
51.
PhD – Doctor of philosophy
52.
pH – Measure of activity of hydrogen ion in a solution
53.
H3O+ - Oxonium
54.
H+ - Hydrogen ion
55.
OH - Hydroxide
56.
aq – Aqueous
57.
Si(OH)4 – Silicic acid
58.
H2O – Water
59.
PO43- - Phosphate ion
60.
h – hour
61.
IGF – Insulin growth factor
62.
TGFβ – Transforming growth factor beta
63.
FDA - Food and Drug Administration
64.
MEP® – Middle ear prosthesis
65.
ERMI® – Endosseous ridge maintenance implant
66.
BG-HCA – Hydroxy apatite carbonate coated bioglass
67.
UBG – Unmodified Bioglass
68.
PMMA – Poly methyl methacrylate
69.
mm - Millimeter
70.
BAG – Bioactive glass
71.
µm - Micrometer
72.
CT – Computed tomography
73.
MRI – Magnetic resonance imaging
96
74.
PET – Positron emission tomography
75.
cm2 – Centimeter square
76.
ROI – Region of interest
77.
HU – Housnfield units
78.
CSF – Cerebrospinal fluid
97
DEFINITIONS AND SYNONYMS
1. Bioactive material: A bioactive material is defined as one that elicits a specific
biological response at the interface of the material that results in the formation
of a bond between the tissues and the material.
2. Bioactive glasses synonymous with Bioglass.
3. Glass ceramics: Polycrystalline ceramics made by controlled crystallization of
glasses, such as Bioglass® and Ceravital®. Some are formulated to have the
ability to form chemical bonds with hard and soft tissues.
4. Bioactive ceramics synonymous with Bio-ceramics and Glass-ceramics.
5. Interface: The area where two immiscible phases of a dispersion presenting in
the same or different states of matter come into contact.
6. Osteoconduction: It refers to the integration of the scaffold or graft material
into the site and its eventual remodeling and replacement.
7. Osteoproduction: Is the production of bone material by cells.
8. Osteoinduction: It is the use of growth factors that draw additional osteogene
cells to the site.
9. Mechanical stimulation: It appears to be a critical factor in the development of
biologically and mechanically optimal bone tissue.
98
REFERENCE
1.
DeLuca L, Raszewski R, Tresser N, Guyuron B. The fate of preserved
autogenous bone graft. Plastic & Reconstructive Surgery. 1997; 99: 13241328.
2.
Rawashdeh MA, Telfah H. Secondary alveolar bone grafting: the dilemma
of donor site selection and morbidity. British Journal of Oral & Maxillofacial
Surgery. 2008; 46: 665-670.
3.
Chen TM, Wang HJ, Chen SL, Lin FH. Reconstruction of post-traumatic
frontal-bone depression using hydroxyapatite cement. Annals of Plastic
Surgery. 2004; 52: 303-308; discussion 309.
4.
Hench LL, West JK. Biological application of bioactive glasses. Life
Chemistry Reports. 1996; 13: 187-241.
5.
Hench LL. Bioactive glass coatings. In: Hench LL, Wilson J, editors. An
introduction to bioceramics. Singapore: World Scientific; 1993: 239-259.
6.
Cao W, Hench LL. Bioactive materials. Ceramics International. 1996; 22:
493-507.
7.
Williams DF. On the mechanisms of biocompatibility. Biomaterials. 2008;
29: 2941-2953.
8.
Williams D. Revisiting the definition of biocompatibility. Medical Device
Technology. 2003; 14: 10-13.
9.
Dušková M, Šmahel Z, Vohradník M, Tvrdek M, Mazánek J, Kozák J,
Kot'ová M, Strnadel T. Bioactive glass-ceramics in facial skeleton
contouring. Aesthetic Plastic Surgery. 2002; 26: 274-283.
10.
Thyagi S. Glasses and glass ceramics as biomaterials [M Tech thesis].
Thapar University, Patiala, Punjab. 2007.
99
11.
Bellucci D, Cannillo V, Sola A. A new bioactive glass composition for
bioceramic scaffolds. Journal of Ceramic Science Technology. 2010; 1:
33-40.
12.
Rawlings RD. Bioactive glasses and glass-ceramics. Clinical Materials.
1993; 14: 155-179.
13.
Brånemark PI, Hansson BO, Adell R, Breine U, Lindström J, Hallén O,
Öhman A. Osseointegrated titanium implants in the treatment of the
edentulous jaw. Experience from a 10-year period. Scandinavian Journal
of Plastic and Reconstructive Surgery and Hand Surgery. Supplement.
1977; 16: 1-132.
14.
Albrektsson T, Brånemark PI, Hansson HA, Lindström J. Osseointegrated
titanium implants. Requirements for ensuring a long-lasting, direct bone-toimplant anchorage in man. Acta Orthopaedica Scandinavica. 1981; 52:
155-170.
15.
Piotrowski G, Hench LL, Allen WC, Miller GJ. Mechanical studies of the
bone bioglass interfacial bond. Journal of Biomedical Materials Research.
1975; 9: 47-61.
16.
Thompson ID, Hench LL. Mechanical properties of bioactive glasses,
glass-ceramics and composites. Proceedings of the Institution of
Mechnical Engineers, Part H: Journal of Engineering in Medicine. 1998;
212: 127-136.
17.
Hench LL. The story of Bioglass. Journal of Materials Science: Materials in
Medicine. 2006; 17: 967-978.
100
18.
Hench LL, Splinter RJ, Allen WC, Greenlee TK. Bonding mechanisms at
the interface of ceramic prosthetic materials. Journal of Biomedical
Materials Research. 1971; 5: 117-141.
19.
Hench LL, Clark AE, Schaake HF. Effects of microstructure on the
radiation stability of amorphous semiconductors. Journal of NonCrystalline Solids. 1972; 8–10: 837-843.
20.
Hench LL, Paschall HA. Direct chemical bond of bioactive glass-ceramic
materials to bone and muscle. Journal of Biomedical Materials Research.
1973; 7: 25-42.
21.
Hench LL, Paschall HA. Histochemical responses at a biomaterial's
interface. Journal of Biomedical Materials Research. 1974; 8: 49-64.
22.
Hench LL, Clark AE. Adhesion to bone. In: Williams DF, editor.
Biocompatibility of Orthopaedic Implants vol. 2. Boca Raton, Florida: CRC
Press; 1982: 129-170.
23.
Hench LL. Development of a new biomaterial prosthetic device. In: Ghista
DN, Roaf R, editors. Orthopaedic Mechanics: Procedures and Devices.
London: Academic Press Inc.; 1978: 287-316.
24.
Hench LL, Pantano CG, Buscemi PJ, Greenspan DC. Analysis of bioglass
fixation of hip prostheses. Journal of Biomedical Materials Research.
1977; 11: 267-282.
25.
Weinstein
AM,
Klawitter
JJ,
Cook
SD.
Implant-bone
interface
characteristics of bioglass dental implants. Journal of Biomedical Materials
Research. 1980; 14: 23-29.
101
26.
Dimitriou R, Jones E, McGonagle D, Giannoudis PV. Bone regeneration:
current concepts and future directions. BioMed Central Medicine. 2011; 9:
66.
27.
Hench LL. Bioceramics: from concept to clinic. Journal of the American
Ceramic Society. 1991; 74: 1487-1510.
28.
Wheeler DL, Eschbach EJ, Hoellrich RG, Montfort MJ, Chamberland DL.
Assessment of resorbable bioactive material for grafting of critical-size
cancellous defects. Journal of Orthopaedic Research. 2000; 18: 140-148.
29.
Hench LL, Polak JM, Xynos ID, Buttery LDK. Bioactive materials to control
cell cycle. Materials Research Innovations. 2000; 3: 313-323.
30.
Xynos ID, Hukkanen MVJ, Batten JJ, Buttery LDK, Hench LL, Polak JM.
Bioglass 45S5 stimulates osteoblast turnover and enhances bone
formation In vitro: implications and applications for bone tissue
engineering. Calcified Tissue International. 2000; 67: 321-329.
31.
Xynos ID, Edgar AJ, Buttery LDK, Hench LL, Polak JM. Ionic products of
bioactive glass dissolution increase proliferation of human osteoblasts and
induce insulin-like growth factor II mRNA expression and protein
synthesis. Biochemical & Biophysical Research Communications. 2000;
276: 461-465.
32.
Xynos ID, Edgar AJ, Buttery LDK, Hench LL, Polak JM. Gene-expression
profiling of human osteoblasts following treatment with the ionic products
of Bioglass 45S5 dissolution. Journal of Biomedical Materials Research.
2001; 55: 151-157.
102
33.
Maroothynaden J, Hench LL. Effect of Bioglass® repeat dosage on
mineralization of embryonic bone in vitro. Key Engineering Materials.
2001; 192-195: 575-588.
34.
Xynos ID, Edgar AJ, Buttery LDK, Hench LL, Polak JM. Gene activating
glasses. Proceedings of the International Congress on Glass; Edinburg,
Scotland. 2001: 226-233.
35.
Oonishi H, Hench LL, Wilson J, Sugihara F, Tsuji E, Matsuura M, Kin S,
Yamamoto T, Mizokawa S. Quantitative comparison of bone growth
behavior in granules of Bioglass, A-W glass-ceramic, and hydroxyapatite.
Journal of Biomedical Materials Research. 2000; 51: 37-46.
36.
Oonishi H, Kushitani S, Yasukawa E, Iwaki H, Hench LL, Wilson J, Tsuji E,
Sugihara T. Particulate bioglass compared with hydroxyapatite as a bone
graft substitute. Clinical Orthopaedics & Related Research. 1997: 316-325.
37.
Fujishiro Y, Oonishi H, Hench LL. Quantitative comparison of in vivo bone
generation with particulate bioglass and hydroxyapatite as a bone graft
substitute. In: Sedel L, Rey C, editors. Proceedings of the 10th
International Symposium on Ceramics in Medicine, Bioceramics 10.
Oxford, London: Pergamon; 1997: 283-288.
38.
Gerhardt LC, Boccaccini AR. Bioactive glass and glass-ceramic scaffolds
for bone tissue engineering. Materials. 2010; 3: 3867-3910.
39.
Hench LL. Bioceramics. Journal of the American Ceramic Society. 1998;
81: 1705-1728.
40.
Lovelace TB, Mellonig JT, Meffert RM, Jones AA, Nummikoski PV,
Cochran DL. Clinical evaluation of bioactive glass in the treatment of
103
periodontal osseous defects in humans. Journal of Periodontology. 1998;
69: 1027-1035.
41.
Hench LL, Jones JR, Sepulveda P. Bioactive materials for tissue
engineering scaffolds In: Polak JM, Hench LL, Kemp P, editors. Future
Strategies for Tissue and Organ Replacement. London: Imperial College
Press; 2002: 3-24.
42.
Hench LL, Best S. Ceramics, glasses, and glass-ceramics In: Ratner BD,
Hoffman AS, Schoen FJ, Lemons JE, editors. Biomaterials science : an
introduction to materials in medicine San Diego, California: Elsevier
Academic Press; 2004: 153-169.
43.
Hench LL, Polak JM. Third-generation biomedical materials. Science.
2002; 295: 1014-1017.
44.
Wilson
J,
Pigott
GH,
Schoen
FJ,
Hench
LL.
Toxicology
and
biocompatibility of bioglasses. Journal of Biomedical Materials Research.
1981; 15: 805-817.
45.
Wilson J, Noletti D. Bonding of soft tissues to Bioglass®. In: Yamamuro T,
Hench LL, Wilson J, editors. Handbook of Bioactive Ceramics vol. 1:
Bioactive Glasses and Glass-Ceramics. Boca Raton, Florida: CRC Press;
1990: 283-302.
46.
Habal MB, Powell RD. Biophysical evaluation of the tumorigenic response
to implanted polymers. Journal of Biomedical Materials Research. 1980;
14: 447-454.
47.
Greenspan DC, Hench LL. Chemical and mechanical behavior of bioglasscoated alumina. Journal of Biomedical Materials Research. 1976; 10: 503509.
104
48.
Gross UM, Strunz V. The anchoring of glass ceramics of different solubility
in the femur of the rat. Journal of Biomedical Materials Research. 1980;
14: 607-618.
49.
Gross U, Strunz V. The interface of various glasses and glass ceramics
with a bony implantation bed. Journal of Biomedical Materials Research.
1985; 19: 251-271.
50.
Jones JR, Gentleman E, Polak J. Bioactive glass scaffolds for bone
regeneration. Elements. 2007; 3: 393-399.
51.
Itälä A, Ylänen HO, Yrjans J, Heino T, Hentunen T, Hupa M, Aro HT.
Characterization of microrough bioactive glass surface: surface reactions
and osteoblast responses in vitro. Journal of Biomedical Materials
Research. 2002; 62: 404-411.
52.
Ebisawa Y, Kokubo T, Ohura K, Yamamuro T. Bioactivity of CaO·SiO 2based glasses: in vitro evaluation. Journal of Materials Science: Materials
in Medicine. 1990; 1: 239-244.
53.
Ohura K, Nakamura T, Yamamuro T, Ebisawa Y, Kokubo T, Kotoura Y,
Oka M. Bioactivity of CaO·SiO2 glasses added with various ions. Journal
of Materials Science: Materials in Medicine. 1992; 3: 95-100.
54.
Kokubo T, Kushitani H, Sakka S, Kitsugi T, Yamamuro T. Solutions able to
reproduce in vivo surface-structure changes in bioactive glass-ceramic AW. Journal of Biomedical Materials Research. 1990; 24: 721-734.
55.
Ohtsuki C, Kukubo T, Yamamuro T. Mechanism of apatite formation on
CaO-SiO2-P2O5 glasses in simulating body fluid. Journal of Non-Crystalline
Solids. 1992; 143: 84-92.
105
56.
Ogino M, Ohuchi F, Hench LL. Compositional dependence of the
formation of calcium phosphate films on bioglass. Journal of Biomedical
Materials Research. 1980; 14: 55-64.
57.
Li R, Clark AE, Hench LL. An investigation of bioactive glass powders by
sol-gel processing. Journal of Applied Biomaterials. 1991; 2: 231-239.
58.
Walker MM. An investigation into the bonding mechanisms of Bioglass [M
S Thesis]. University of Florida, Gainesville, Florida. 1977.
59.
Costantini A, Fresa R, Buri A, Branda F. Effect of the substitution of Y2O3
for CaO on the bioactivity of 2.5CaO · 2SiO2 glass. Biomaterials. 1997; 18:
453-458.
60.
Filgueiras MR, La Torre G, Hench LL. Solution effects on the surface
reactions of a bioactive glass. Journal of Biomedical Materials Research.
1993; 27: 445-453.
61.
Lockyer MWG, Holland D, Dupree R. NMR investigation of the structure of
some bioactive and related glasses. Journal of Non-Crystalline Solids.
1996; 188: 207-219.
62.
Ohtsuki C, Kushitani H, Kokubo T, Kotani S, Yamamuro T. Apatite
formation on the surface of Ceravital-type glass-ceramic in the body.
Journal of Biomedical Materials Research. 1991; 25: 1363-1370.
63.
Vogel W, Höhland W. Development, structure, properties and applications
of glass-ceramics for medicine. Journal of Non-Crystalline Solids. 1990;
123: 349-353.
64.
Kasuga T, Nakagawa K, Yoshida M, Miyade E. Compositional
dependence of formation of an apatite layer on glass-ceramics in
106
simulated physiological solution. Journal of Material Science. 1987; 22:
3721-3724.
65.
Kokubo T, Ito S, Sakka S, Yamamuro T. Formation of a high-strength
bioactive glass-ceramic in the system MgO-CaO-SiO2-P2O5. Journal of
Material Science. 1986; 21: 536-540.
66.
Kokubo T. Surface chemistry of bioactive glass-ceramics. Journal of NonCrystalline Solids. 1990; 120: 138-151.
67.
West JK, Hench LL. Reaction kinetics of bioactive ceramics. In:
Yamamura T, Kokubo T, Nakamuro T, editors. Proceedings of the 5th
Symposium on Ceramics in Medicine, Bioceramics 5. Kyoto, Japan:
Kobonshi Kankokai Inc.; 1992: 75-86.
68.
Roman J, Salinas AJ, Vallet-Regí M, Oliveira JM, Correia RN, Fernandes
MH. Role of acid attack in the in vitro bioactivity of a glass-ceramic of the
3CaO·P2O5-CaO·SiO2-CaO·MgO·2SiO2 system. Biomaterials. 2001; 22:
2013-2019.
69.
Liu DM, Chou HM, Wu JD. Plasma-sprayed hydroxyapatite coating: effect
of different calcium phosphate ceramics. Journal of Materials Science:
Materials in Medicine. 1994; 5: 147-153.
70.
Oliveira JM, Correia RN, Fernandes MH. Surface modifications of a glass
and a glass-ceramic of the MgO-3CaO · P2O5-SiO2 system in a simulated
body fluid. Biomaterials. 1995; 16: 849-854.
71.
Lin C-C, Li-Chen H, Shen P. Na2CaSi2O6-P2O5 based bioactive glasses.
Part 1: Elasticity and structure. Journal of Non-Crystalline Solids. 2005;
351: 3195-3203.
107
72.
Serra J, González P, Liste S, Serra C, Chiussi S, León B, Pérez-Amor M,
Ylänen H, Hupa M. FTIR and XPS studies of bioactive silica based
glasses. Journal of Non-Crystalline Solids. 2003; 332: 20-27.
73.
Peitl FO, LaTorre GP, Hench LL. Effect of crystallization on apatite-layer
formation of bioactive glass 45S5. Journal of Biomedical Materials
Research. 1996; 30: 509-514.
74.
Leonor IB, Ito A, Onuma K, Kanzaki N, Zhong Z, Greenspan D, Reis RL.
In situ AFM study of the mechanisms involved on calcium-phosphate film
formation on partially crystallized Bioglass® and on hydroxylapatite
immersed in a simulated body fluid. Key Engineering Materials. 2002; 218220: 291-294.
75.
Kim CY, Jee SS. Hydroxyapatite formation on bioactive-glazed alumina.
Journal of European Ceramic Society. 2003; 23: 1803-1811.
76.
Singh K, Bahadur D. Characterization of SiO2-Na2O-Fe2O3-CaO-P2O5-B2O3
glass ceramics. Journal of Materials Science: Materials in Medicine. 1999;
10: 481-484.
77.
Li G, Feng S, Zhou D. Magnetic bioactive glass ceramic in the system
CaO–P2O5–SiO2–MgO–CaF2–MnO2–Fe2O3 for hyperthermia treatment of
bone tumor. Journal of Materials Science: Materials in Medicine. 2011; 22:
2197-2206.
78.
Franks K, Abrahams I, Georgiou G, Knowles JC. Investigation of thermal
parameters and crytallisation in a ternary CaO–Na2O–P2O5-based glass
system. Biomaterials. 2001; 22: 497-501.
108
79.
Ahmed I, Lewis M, Olsen I, Knowles JC. Phosphate glasses for tissue
engineering: Part 2. Processing and characterisation of a ternary-based
P2O5–CaO–Na2O glass fibre system. Biomaterials. 2004; 25: 501-507.
80.
Begum N, Rajendran V, Heimo Y. Effect of thermal treatment on physical
properties of bioactive glasses. Materials Chemistry and Physics. 2006;
96: 409-417.
81.
Gayathri Devi AV, Rajendran V, Rajendran N. Structure, solubility and
bioactivity in TiO2-doped phosphate-based bioglasses and glass–
ceramics. Materials Chemistry and Physics. 2010; 124: 312-318.
82.
Kasuga T. Bioactive calcium pyrophosphate glasses and glass-ceramics.
Acta Biomaterialia. 2005; 1: 55-64.
83.
Olmo N, Martín AI, Salinas AJ, Turnay J, Vallet-Regí M, Lizarbe MA.
Bioactive sol–gel glasses with and without a hydroxycarbonate apatite
layer as substrates for osteoblast cell adhesion and proliferation.
Biomaterials. 2003; 24: 3383-3393.
84.
Griss P, Greenspan DC, Heimke G, Krempien B, Buchinger R, Hench LL,
Jentschura G. Evaluation of a bioglass-coated Al2O3 total hip prosthesis in
sheep. Journal of Biomedical Materials Research. 1976; 10: 511-518.
85.
Gross U, Kinne R, Schmitz HJ, Strunz V. The response of bone to surface
active glass/glass-ceramics. In: Williams DF, editor. Critical Reviews in
Biocompatibility vol.4. Boca Ranton, Florida: CRC Press 1988: 2.
86.
Nakamura T, Yamamuro T, Higashi S, Kokubo T, Itoo S. A new glassceramic for bone replacement: Evaluation of its bonding to bone tissue.
Journal of Biomedical Materials Research. 1985; 19: 685-698.
109
87.
Yoshii S, Kakutani Y, Yamamuro T, Nakamura T, Kitsugi T, Oka M,
Kokubo T, Takagi M. Strength of bonding between A-W glass-ceramic and
the surface of bone cortex. Journal of Biomedical Materials Research.
1988; 22: 327-338.
88.
Yamamuro T. A/W Glass-Ceramic:Clinical Applications. In: Yamamuro T,
Hench LL, Wilson J, editors. Handbook of Bioactive Ceramics vol. 1:
Bioactive Glass and Glass Ceramics. Boca Ranton, Florida CRC Press
1990: 89.
89.
Neo M, Kotani S, Nakamura T, Yamamuro T, Ohtsuki C, Kokubo T, Bando
Y. A comparative study of ultrastructures of the interfaces between four
kinds of surface-active ceramic and bone. Journal of Biomedical Materials
Research. 1992; 26: 1419-1432.
90.
Andersson ÖH, Liu G, Karlsson KH, Niemi L, Miettinen J, Juhanoja J. In
vivo behaviour of glasses in the SiO2-Na2O-CaO-P2O5-Al2O3-B2O3 system.
Journal of Materials Science: Materials in Medicine. 1990; 1: 219-227.
91.
Kangasniemi K, Yli-Urpo A. Biological response to glasses in the SiO2Na2O-CaO-P2O5-B2O3-Al2O3 system. In: Yamamuro T, Hench LL, Wilson
J, editors. Handbook of Bioactive Ceramics vol.1: Bioactive Glasses and
Glass-Ceramics. Boca Raton, Florida: CRC Press; 1990: 97.
92.
Lin CC, Chen SF, Leung KS, Shen P. Effects of CaO/P 2O5 ratio on the
structure and elastic properties of SiO2–CaO–Na2O–P2O5 bioglasses.
Journal of Materials Science: Materials in Medicine. 2012; 23: 245-258.
93.
Clark AE, Pantano CG, Hench LL. Corrosion of glass. New York: Books
for Industry. 1979.
110
94.
Greenspan DC, Zhong JP, LaTorre GP. Effect of surface area to volume
ratio on in vitro surface reactions of bioactive glass particulates. In:
Andersson OH, Happonen RP, Yli-Urpo A, editors. Proceedings of the 7th
International Symposium on Ceramics in Medicine, Bioceramics 7. Oxford,
London: Butterworth-Heinemann; 1994: 55-60.
95.
Greenspan DC, Zhong JP, Chen ZF, LaTorre GP. The evaluation of
degradability of melt and sol–gel derived Bioglass® in vitro. In: Sedel L,
Rey C, editors. Proceedings of the 10th International Symposium on
Ceramics in Medicine, Bioceramics 10. Oxford, London: Pergamon; 1997:
391-394.
96.
Greenspan DC, Zhong JP, Wheeler DL. Bioactivity and biodegradability:
Melt vs sol.gel derived Bioglass® in vitro and in vivo. In: LeGeros RZ,
LeGeros JP, editors. Proceedings of the 11th International Symposium on
Ceramics in Medicine, Bioceramics 11. New York: World Scientific; 1998:
345-348.
97.
Peltola MJ, Kinnunen I, Aitasalo KMJ. Reconstruction of orbital wall
defects with bioactive glass plates. Journal of Oral & Maxillofacial Surgery.
2008; 66: 639-646.
98.
Francis L. Biosynthesis of Polyhydroxyalkanoates and their medical
applications [PhD Thesis]. University of Wesminster, England. 2011.
99.
Schepers EJ, Ducheyne P, Barbier L, Schepers S. Bioactive glass
particles of narrow size range: a new material for the repair of bone
defects. Implant Dentistry. 1993; 2: 151-156.
100.
Zhong JP, LaTorre GP, Hench LL. The kinetics of bioactive ceramics. In:
Andersson OH, Yli-Urpo A, editors. Proceedings of the 7th International
111
Symposium on Ceramics in Medicine, Bioceramics 7. Oxford, London:
Butterworth-Heinemann; 1994: 61-66.
101.
Rinehart JD, Taylor TD, Tian Y, Latour RA. Real-time dissolution
measurement of sized and unsized calcium phosphate glass fibers.
Journal of Biomedical Materials Research. 1999; 48: 833-840.
102.
Pereira MM, Clark AE, Hench LL. Effect of texture on the rate of
hydroxyapatite formation on gel-silica surface. Journal of the American
Ceramic Society. 1995; 78: 2463-2468.
103.
Mazer JJ, Walther JV. Dissolution kinetics of silica glass as a function of
pH between 40 and 85°C. Journal of Non-Crystalline Solids. 1994; 170:
32-45.
104.
Douglas RW, El-Shamy TMM. Reactions of glasses with aqueous
solutions. Journal of the American Ceramic Society. 1967; 50: 1-8.
105.
Tadjoedin ES, De Lange GL, Holzmann PJ, Kuiper L, Burger EH.
Histological observations on biopsies harvested following sinus floor
elevation using a bioactive glass material of narrow size range. Clinical
Oral Implants Research. 2000; 11: 334-344.
106.
Aitasalo KMJ, Peltola MJ. Bioactive glass hydroxyapatite in fronto-orbital
defect reconstruction. Plastic & Reconstructive Surgery. 2007; 120: 19631972; discussion 1973-1974.
.107. Hench LL. Bioactive materials: The potential for tissue regeneration.
Founders Award, Society for Biomaterials 24th annual meeting; San
Diego, California. 1998: 511-518.
112
108.
Price N, Bendall SP, Frondoza C, Jinnah RH, Hungerford DS. Human
osteoblast-like cells (MG63) proliferate on a bioactive glass surface.
Journal of Biomedical Materials Research. 1997; 37: 394-400.
109.
Norton MR, Wilson J. Dental implants placed in extraction sites implanted
with bioactive glass: human histology and clinical outcome. The
International Journal of Oral and Maxillofacial Implants. 2002; 17: 249-257.
110.
Geyer G, Schott C, Schwarzkopf A. Modification of bacterial growth by
alloplastic bone substitutes. Deutsche Gesellschaft für Hals-Nasen-OhrenHeilkunde, Kopf- und Hals-Chirurgie. 1999; 47: 25-32.
111.
Cornell CN. Osteoconductive materials and their role as substitutes for
autogenous bone grafts. Orthopedic Clinics of North America. 1999; 30:
591-598.
112.
Kurashina K, Kurita H, Kotani A, Takeuchi H, Hirano M. In vivo study of a
calcium
phosphate
cement
consisting
of
alpha-tricalcium
phosphate/dicalcium phosphate dibasic/tetracalcium phosphate monoxide.
Biomaterials. 1997; 18: 147-151.
113.
Laurencin CT, Attawia M, Borden MD. Advancements in tissue engineered
bone substitutes. Current Opinion in Orthopaedics. 1999; 10: 445-451.
114.
Weibrich G, Gnoth SH, Kunkel M, Trettin R, Werner HD, Wagner W.
Roentgen
spectrometry
comparison
of
currently
available
bone
substitutes. Mund-, Kiefer- und Gesichtschirurgie. 1999; 3: 92-97.
115.
Yang CY, Wang BC, Chang WJ, Chang E, Wu JD. Mechanical and
histological evaluations of cobalt-chromium alloy and hydroxyapatite
plasma-sprayed coatings in bone. Journal of Materials Science: Materials
in Medicine. 1996; 7: 167-174.
113
116.
Burnie J, Gilchrist T. Controlled release glass (C.R.G.) – a new
biomaterial. In: Vincenzini P, editor. Ceramics in Surgery. Amsterdam:
Elsevier; 1983: 169-176.
117.
Choueka J, Charvet JL, Alexander H, Oh YO, Joseph G, Blumenthal NC,
LaCourse WC. Effect of annealing temperature on the degradation of
reinforcing fibers for absorbable implants. Journal of Biomedical Materials
Research. 1995; 29: 1309-1315.
118.
Schepers EJ, Ducheyne P. Bioactive glass particles of narrow size range
for the treatment of oral bone defects: a 1-24 month experiment with
several materials and particle sizes and size ranges. Journal of Oral
Rehabilitation. 1997; 24: 171-181.
119.
Malard O, Bouler JM, Guicheux J, Heymann D, Pilet P, Coquard C,
Daculsi G. Influence of biphasic calcium phosphate granulometry on bone
ingrowth, ceramic resorption, and inflammatory reactions: Preliminary in
vitro and in vivo study. Journal of Biomedical Materials Research. 1999;
46: 103-111.
120.
Brewster NT, Gillespie WJ, Howie CR, Madabhushi SP, Usmani AS,
Fairbairn DR. Mechanical considerations in impaction bone grafting.
Journal of Bone & Joint Surgery. British Volume. 1999; 81: 118-124.
121.
Griffon DJ. Evaluation of osteoproductive biomaterials: Allograft, bone
inducing agent, bioactive glass, and ceramics [Academic Dissertation].
University of Helsinki, Helsinki. 2002.
122.
Lew D, Farrell B, Bardach J, Keller J. Repair of craniofacial defects with
hydroxyapatite cement. Journal of Oral & Maxillofacial Surgery. 1997; 55:
1441-1449; discussion 1449-1451.
114
123.
Tägil M. The morselized and impacted bone graft. Animal experiments on
proteins,
impaction
and
load.
Acta
Orthopaedica
Scandinavica.
Supplementum. 2000; 290: 1-40.
124.
Merwin GE. Review of bioactive materials for otologic and maxillofacial
applications. In: Yamamuro T, Hench LL, Wilson J, editors. Handbook of
Bioactive Ceramics vol.1. Boca Raton, Florida: CRC Press; 1990: 323.
125.
Bonfield W, Hastings GW, Tanner KE. Bioceramics. Oxford: ButterworthHeineman. 1991.
126.
Hench LL, Wilson J, Greenspan DC. Bioglass®: a short history and
bibliography. Journal of the Australian Ceramic Society. 2004; 40: 1-42.
127.
Hench LL, Ethridge EC. Biomaterials : an interfacial approach. New York:
Academic Press. 1982.
128.
Hum J, Boccaccini AR. Bioactive glasses as carriers for bioactive
molecules and therapeutic drugs: a review. Journal of Materials Science:
Materials in Medicine. 2012.
129.
Porous glass. Wikipedia, The Free Encyclopedia. May 5, 2012, 23:51
UTC.
Available
at:
http://en.wikipedia.org/w/index.php?title=Porous_glass&oldid=490884754.
Accessed July 30, 2012.
130.
Jefferies SR, Appleby D, Boston D, Pameijer CH, Lööf J. Clinical
performance of a bioactive dental luting cement--a prospective clinical pilot
study. Journal of Clinical Dentistry. 2009; 20: 231-237.
131.
Banerjee A, Hajatdoost-Sani M, Farrell S, Thompson I. A clinical
evaluation and comparison of bioactive glass and sodium bicarbonate airpolishing powders. Journal of Dentistry. 2010; 38: 475-479.
115
132.
Mistry S, Kundu D, Datta S, Basu D, Soundrapandian C. Indigenous
hydroxyapatite coated and bioactive glass coated titanium dental implant
system - Fabrication and application in humans. Journal of Indian Society
of Periodontolgy. 2011; 15: 215-220.
133.
Brook IM, Hatton PV. Glass-ionomers: bioactive implant materials.
Biomaterials. 1998; 19: 565-571.
134.
Höland W, Rheinberger V, Apel E, van 't Hoen C, Höland M, Dommann A,
Obrecht M, Mauth C, Graf-Hausner U. Clinical applications of glassceramics in dentistry. Journal of Materials Science: Materials in Medicine.
2006; 17: 1037-1042.
135.
Vallet-Regí M, Ruiz-Hernández E. Bioceramics: from bone regeneration to
cancer nanomedicine. Advanced Materials. 2011; 23: 5177-5218.
136.
El-Ghannam A. Bone reconstruction: from bioceramics to tissue
engineering. Expert Review of Medical Devices. 2005; 2: 87-101.
137.
Vallet-Regí M. Revisiting ceramics for medical applications. Dalton
Transactions. 2006: 5211-5220.
138.
Gosain AK. Bioactive glass for bone replacement in craniomaxillofacial
reconstruction. Plastic & Reconstructive Surgery. 2004; 114: 590-593.
139.
Wilson J, Low SB. Bioactive ceramics for periodontal treatment:
comparative studies in the Patus monkey. Journal of Applied Biomaterials.
1992; 3: 123-129.
140.
Kitsugi T, Yamamuro T, Kokubo T. Bonding behavior of a glass-ceramic
containing apatite and wollastonite in segmental replacement of the rabbit
tibia under load-bearing conditions. Journal of Bone and Joint Surgery.
American Volume. 1989; 71: 264-272.
116
141.
Wheeler DL, Stokes KE, Hoellrich RG, Chamberland DL, McLoughlin SW.
Effect of bioactive glass particle size on osseous regeneration of
cancellous defects. Journal of Biomedical Materials Research. 1998; 41:
527-533.
142.
Bergman SA, Litkowski LJ. Bone in-fill of non-healing calvarial defects
using particulate Bioglass and autogenous bone. In: Wilson J, Hench LL,
Greenspan DC, editors. Proceedings of the 8th International Symposium
on Ceramics in Medicine: Bioceramics 8. Oxford, London: Pergamon;
1995: 17-21.
143.
Vrouwenvelder WCA, Groot CG, de Groot K. Histological and biochemical
evaluation of osteoblasts cultured on bioactive glass, hydroxylapatite,
titanium alloy, and stainless steel. Journal of Biomedical Materials
Research. 1993; 27: 465-475.
144.
Peltola MJ, Aitasalo KMJ, Suonpää JTK, Yli-Urpo A, Laippala PJ,
Forsback AP. Frontal sinus and skull bone defect obliteration with three
synthetic bioactive materials. A comparative study. Journal of Biomedical
Materials Research Part B: Applied Biomaterials. 2003; 66: 364-372.
145.
Cancian DC, Hochuli-Vieira E, Marcantonio RA, Marcantonio E. Use of
BioGran and Calcitite in bone defects: histologic study in monkeys (Cebus
apella). The International Journal of Oral and Maxillofacial Implants. 1999;
14: 859-864.
146.
Cancian DC, Hochuli-Vieira E, Marcantonio RA, Garcia IR. Utilization of
autogenous bone, bioactive glasses, and calcium phosphate cement in
surgical mandibular bone defects in Cebus apella monkeys. The
International Journal of Oral and Maxillofacial Implants. 2004; 19: 73-79.
117
147.
El-Ghannam A, Amin H, Nasr T, Shama A. Enhancement of bone
regeneration and graft material resorption using surface-modified bioactive
glass in cortical and human maxillary cystic bone defects. International
Journal of Oral & Maxillofacial Implants. 2004; 19: 184-191.
148.
Matsuoka H, Akiyama H, Okada Y, Ito H, Shigeno C, Konishi J, Kokubo T,
Nakamura T. In vitro analysis of the stimulation of bone formation by highly
bioactive apatite- and wollastonite-containing glass-ceramic: released
calcium ions promote osteogenic differentiation in osteoblastic ROS17/2.8
cells. Journal of Biomedical Materials Research. 1999; 47: 176-188.
149.
Beeson WH. Plaster of paris as an alloplastic implant in the frontal sinus.
Archives of Otolaryngology. 1981; 107: 664-669.
150.
Stoor P, Söderling E, Salonen JI. Antibacterial effects of a bioactive glass
paste on oral microorganisms. Acta Odontologica Scandinavica. 1998; 56:
161-165.
151.
Peltola MJ, Aitasalo KMJ, Suonpää JTK, Varpula MJ, Yli-Urpo A. Bioactive
glass S53P4 in frontal sinus obliteration: a long-term clinical experience.
Head & Neck. 2006; 28: 834-841.
152.
Stoor P, Söderling E, Anderrson ÖH, Yli-Urpo A. Interactions between
frontal sinusitis-associated pathogen Haemophilus influenza and bioactive
glass S53P4. In: Wilson J, Hench LL, Greenspan DC, editors. Proceedings
of the 8th International Symposium on Ceramics in Medicine: Bioceramics
8. Oxford, London: Pergamon; 1995: 253-258.
153.
Munukka E, Leppäranta O, Korkeamäki M, Vaahtio M, Peltola T, Zhang D,
Hupa L, Ylänen H, Salonen J, Viljanen M and others. Bactericidal effects
118
of bioactive glasses on clinically important aerobic bacteria. Journal of
Materials Science: Materials in Medicine. 2008; 19: 27-32.
154.
Leppäranta O, Vaahtio M, Peltola T, Zhang D, Hupa L, Hupa M, Ylänen H,
Salonen JI, Viljanen MK, Eerola E. Antibacterial effect of bioactive glasses
on clinically important anaerobic bacteria in vitro. Journal of Materials
Science: Materials in Medicine. 2008; 19: 547-551.
155.
Stoor P, Grénman R. Bioactive glass and turbinate flaps in the repair of
nasal septal perforations. Annals of Otology, Rhinology & Laryngology.
2004; 113: 655-661.
156.
Stoor P, Söderling E, Grénman R. Bioactive glass S53P4 in repair of
septal perforations and its interactions with the respiratory infectionassociated microorganisms Haemophilus influenzae and Streptococcus
pneumoniae. Journal of Biomedical Materials Research. 2001; 58: 113120.
157.
Hollinger JO, Kleinschmidt JC. The critical size defect as an experimental
model to test bone repair materials. The Journal of Craniofacial Surgery.
1990; 1: 60-68.
158.
Schmitz JP, Hollinger JO. The critical size defect as an experimental
model for craniomandibulofacial nonunions. Clinical Orthopaedics &
Related Research. 1986; 205: 299-308.
159.
Bosch C, Melsen B, Vargervik K. Importance of the critical-size bone
defect in testing bone-regenerating materials. Journal of Craniofacial
Surgery. 1998; 9: 310-316.
160.
Livne L, Srouji S. Scaffolds in skeletal repair. In: Sela JJ, Bab IA, editors.
Principles of bone regeneration. New York: Springer; 2012: 97-117.
119
161.
Taba M, Jin Q, Sugai JV, Giannobile WV. Current concepts in periodontal
bioengineering. Orthodontics and Craniofacial Research. 2005; 8: 292302.
162.
Seaborn CD, Nielsen FH. Effects of germanium and silicon on bone
mineralization. Biological Trace Element Research. 1994; 42: 151-164.
163.
Hench LL, Thompson I. Twenty-first century challenges for biomaterials.
Journal of the Royal Society Interface. 2010; 7 Suppl 4: S379-391.
164.
Navarro M, Michiardi A, Castaño O, Planell JA. Biomaterials in
orthopaedics. Journal of the Royal Society Interface. 2008; 5: 1137-1158.
165.
Jugdaohsingh R. Silicon and bone health. The Journal of Nutrition Health
and Aging. 2007; 11: 99-110.
166.
Peltola MJ, Suonpää JTK, Määttänen HS, Varpula MJ, Aitasalo KMJ, YliUrpo A, Laippala PJ. Clinical follow-up method for frontal sinus obliteration
with bioactive glass S53P4. Journal of Biomedical Materials Research.
2001; 58: 54-60.
167.
Elshahat A. Correction of craniofacial skeleton contour defects using
bioactive glass particles. Egyptian Journal of Plastic and Reconstructive
Surgery. 2006; 30: 113-119.
168.
Throndson RR, Sexton SB. Grafting mandibular third molar extraction
sites: a comparison of bioactive glass to a nongrafted site. Oral Surgery,
Oral Medicine, Oral Pathology, Oral Radiology & Endodontics. 2002; 94:
413-419.
169.
Peltola MJ, Vallittu PK, Vuorinen V, Aho AAJ, Puntala A, Aitasalo KMJ.
Novel composite implant in craniofacial bone reconstruction. European
Archives of Oto-Rhino-Laryngology. 2012; 269: 623-628.
120
170.
Cordioli G, Mazzocco C, Schepers E, Brugnolo E, Majzoub Z. Maxillary
sinus floor augmentation using bioactive glass granules and autogenous
bone with simultaneous implant placement. Clinical and histological
findings. Clinical Oral Implants Research. 2001; 12: 270-278.
171.
Peltola MJ, Suonpää JTK, Aitasalo KMJ, Varpula MJ, Yli-Urpo A,
Happonen RP. Obliteration of the frontal sinus cavity with bioactive glass.
Head & Neck. 1998; 20: 315-319.
172.
Wide K, Sipilä J, Suonpää JTK. Report on results of frontal sinus
obliterations in Turku University Central Hospital 1977-1994. Acta
Otolaryngologica. Supplementum. 1997; 529: 184-186.
173.
Gosain AK, Chim H, Arneja JS. Application-specific selection of
biomaterials for pediatric craniofacial reconstruction: developing a rational
approach to guide clinical use. Plastic & Reconstructive Surgery. 2009;
123: 319-330.
174.
Aitasalo KMJ, Kinnunen I, Palmgren J, Varpula M. Repair of orbital floor
fractures with bioactive glass implants. Journal of Oral & Maxillofacial
Surgery. 2001; 59: 1390-1395; discussion 1395-1396.
175.
Suominen E, Kinnunen J. Bioactive glass granules and plates in the
reconstruction of defects of the facial bones. Scandinavian Journal of
Plastic & Reconstructive Surgery & Hand Surgery. 1996; 30: 281-289.
176.
Pihlstrom BL, Michalowicz B, Atkinson J, Kingman A. Prominent design
issues in oral health clinical trials. In: Gad SC, editor. Clinical Trials
Handbook. Hoboken, NJ: Wiley; 2009: 436.
121
177.
Jordan DR, St Onge P, Anderson RL, Patrinely JR, Nerad JA.
Complications associated with alloplastic implants used in orbital fracture
repair. Ophthalmology. 1992; 99: 1600-1608.
178.
Waris T, Pohjanen T, Törmälä P. Self-reinforced absorbable polylactide
(SR-PLLA) plates in craniofacial surgery. European Journal of Plastic
Surgery. 1994; 17: 236-238.
179.
Rehman I, Hench LL, Bonfield W, Smith R. Analysis of surface layers on
bioactive glasses. Biomaterials. 1994; 15: 865-870.
180.
Cenzi R, Farina A, Zuccarino L, Carinci F. Clinical outcome of 285 Medpor
grafts used for craniofacial reconstruction. The Journal of Craniofacial
Surgery. 2005; 16: 526-530.
181.
Menderes A, Baytekin C, Topcu A, Yilmaz M, Barutcu A. Craniofacial
reconstruction with high-density porous polyethylene implants. The Journal
of Craniofacial Surgery. 2004; 15: 719-724.
182.
Dougherty WR, Wellisz T. The natural history of alloplastic implants in
orbital floor reconstruction: an animal model. Journal of Craniofacial
Surgery. 1994; 5: 26-32; discussion 33.
183.
Citardi MJ, Friedman CD. Nonvascularized autogenous bone grafts for
craniofacial skeletal augmentation and replacement. Otolaryngologic
Clinics of North America. 1994; 27: 891-910.
184.
Enlow DH, Hans MG. Essentials of facial growth. Philadelphia: Saunders;
1996: 57-78.
185.
Lemperle SM, Calhoun CJ, Curran RW, Holmes RE. Bony healing of large
cranial and mandibular defects protected from soft-tissue interposition: A
comparative study of spontaneous bone regeneration, osteoconduction,
122
and cancellous autografting in dogs. Plastic & Reconstructive Surgery.
1998; 101: 660-672.
186.
Kinnunen I, Aitasalo K, Pöllönen M, Varpula M. Reconstruction of orbital
floor fractures using bioactive glass. Journal of Cranio-Maxillofacial
Surgery. 2000; 28: 229-234.
187.
Bergara AR, Itoiz AO. Present status of the surgical treatment of chronic
frontal sinusitis. Archives of Otolaryngology--Head and Neck Surgery.
1958; 61: 271-283.
188.
Montgomery WW, Pierce L. Anterior osteoplastic fat obliteration for frontal
sinus. Transactions of the American Academy of Ophthalmology and
Otolaryngology. 1963; 67: 46-54.
189.
Montgomery WW. The fate of adipose implants in a bony cavity. The
Laryngoscope. 1964; 74: 816-827.
190.
Schenck NL. Frontal sinus disease. III. Experimental and clinical factors in
failure of the frontal osteoplastic operation. The Laryngoscope. 1975; 85:
76-92.
191.
Failla A. Operative management of injuries involving the frontal sinuses: A
study of eighteen operated cases. The Laryngoscope. 1968; 78: 18331852.
192.
Barton RT. The use of synthetic implant material in osteoplastic frontal
sinusotomy. The Laryngoscope. 1980; 90: 47-52.
193.
Lawson W. Frontal sinus. In: Blizer A, Lawson W, Friedman WH, editors.
Surgery of the Paranasal Sinuses. Philadelphia: WB Saunders & Co.;
1991: 183-218.
123
194.
Mcneill RA. Surgical obliteration of the maxillary sinus: A clinical and
experimental study. The Laryngoscope. 1967; 77: 202-217.
195.
Yamagishi M, Ishizuka Y, Nakano Y. Frontoethmoidectomy with ceramic
hydroxyapatite implant in the treatment of mucocele. American Journal of
Rhinology. 1993; 7: 267-271.
196.
Peltola MJ, Suonpää JTK, Aitasalo KMJ, Määttänen H, Andersson O, YliUrpo A, Laippala P. Experimental follow-up model for clinical frontal sinus
obliteration
with
bioactive
glass
(S53P4).
Acta
Otolaryngologica.
Supplementum. 2000; 543: 167-169.
197.
Hardy JM, Montgomery WW. Osteoplastic frontal sinusotomy: an analysis
of 250 operations. Annals of Otology, Rhinology & Laryngology. 1976; 85:
523-532.
198.
Montgomery WW, Van Orman P. The inhibitory effect of adipose tissue on
osteogenesis. Annals of Otology, Rhinology & Laryngology. 1967; 76: 988997.
199.
Peltola MJ, Aitasalo KMJ, Suonpää JTK, Yli-Urpo A, Laippala PJ. In vivo
model for frontal sinus and calvarial bone defect obliteration with bioactive
glass S53P4 and hydroxyapatite. Journal of Biomedical Materials
Research. 2001; 58: 261-269.
200.
Peltola MJ, Suonpää JTK, Andersson H, Määttänen HS, Aitasalo KMJ, YliUrpo A, Laippala PJ. In vitro model for frontal sinus obliteration with
bioactive glass S53P4. Journal of Biomedical Materials Research. 2000;
53: 161-166.
201.
Goodale RL. The rationale of frontal sinus surgery. The Laryngoscope.
1965; 75: 981-987.
124
202.
Tallgren A. The continuing reduction of the residual alveolar ridges in
complete denture wearers: a mixed-longitudinal study covering 25 years.
Journal of Prosthetic Dentistry. 1972; 27: 120-132.
203.
Schepers E, de Clercq M, Ducheyne P, Kempeneers R. Bioactive glass
particulate material as a filler for bone lesions. Journal of Oral
Rehabilitation. 1991; 18: 439-452.
204.
Roth H, Müller W, Spiessl B. Treatment of extensive bone defects in the
jaws
with
hydroxyapatite
granules.
Schweizer
Monatsschrift
fur
Zahnmedizin. 1984; 94: 222-227.
205.
Trottler C, Frenkel G, Rahn R, Thomaidis G, Arndt R. Clinical results of
filling intraoral bone defects with ionomeric porous microimplants (V-Os).
Das Deutsche Zahnärzteblatt. 1991; 100: 742-744.
206.
Quinones CR, Lovelace TB. Utilization of a bioactive synthetic particulate
for periodontal therapy and bone augmentation techniques. Practical
Periodontics & Aesthetic Dentistry. 1997; 9: 1-7.
207.
Sy IP. Alveolar ridge preservation using a bioactive glass particulate graft
in extraction site defects. General Dentistry. 2002; 50: 66-68.
208.
Jones JA, Wei JY, Atwood DA, Chauncey HH. Age-related changes in
alveolar bone repair in adult rats. Gerodontics. 1987; 3: 171-180.
209.
Meister F, Nery EB, Angell DM, Meister RC. Periodontal assessment
following surgical removal of mandibular third molars. General Dentistry.
1986; 34: 120-123.
210.
Block MS, Kent JN. Sinus augmentation for dental implants: the use of
autogenous bone. Journal of Oral & Maxillofacial Surgery. 1997; 55: 12811286.
125
211.
Skoglund A, Hising P, Young C. A clinical and histologic examination in
humans of the osseous response to implanted natural bone mineral. The
International Journal of Oral and Maxillofacial Implants. 1997; 12: 194-199.
212.
Furusawa T, Mizunuma K. Osteoconductive properties and efficacy of
resorbable bioactive glass as a bone-grafting material. Implant Dentistry.
1997; 6: 93-101.
213.
Low SB, King CJ, Krieger J. An evaluation of bioactive ceramic in the
treatment of periodontal osseous defects. The International Journal of
Periodontics and Restorative Dentistry. 1997; 17: 358-367.
214.
Camargo PM, Lekovic V, Weinlaender M, Klokkevold PR, Kenney EB,
Dimitrijevic B, Nedic M, Jancovic S, Orsini M. Influence of bioactive glass
on changes in alveolar process dimensions after exodontia. Oral Surgery,
Oral Medicine, Oral Pathology, Oral Radiology & Endodontics. 2000; 90:
581-586.
215.
Guglielmotti MB, Cabrini RL. Alveolar wound healing and ridge remodeling
after tooth extraction in the rat: A histologic, radiographic, and histometric
study. Journal of Oral & Maxillofacial Surgery. 1985; 43: 359-364.
216.
Marmary Y, Brayer L, Tzukert A, Feller L. Alveolar bone repair following
extraction of impacted mandibular third molars. Oral Surgery, Oral
Medicine, Oral Pathology. 1986; 61: 324-326.
217.
Gatti AM, Ducheyne P, Piattelli A, Schepers E, Trisi P, Chiarini L, Monari
E. Glass Corrosion Layers on Bioactive Glass Granules of Uniform Size
Affect Cellular Function. In: Ducheyne P, Christiansen D, editors.
Proceedings of the 6th International Symposium on Ceramics in Medicine,
Bioceramics 6. Oxford: Pergamon; 1993: 395-400.
126
218.
Nevins ML, Camelo M, Nevins M, King CJ, Oringer RJ, Schenk RK,
Fiorellini JP. Human histologic evaluation of bioactive ceramic in the
treatment of periodontal osseous defects. The International Journal of
Periodontics and Restorative Dentistry. 2000; 20: 458-467.
219.
Tadjoedin ES, De Lange GL, Lyaruu DM, Kuiper L, Burger EH. High
concentrations of bioactive glass material (BioGran®) vs. autogenous
bone for sinus floor elevation. Clinical Oral Implants Research. 2002; 13:
428-436.
220.
Albrektsson T, Zarb G, Worthington P, Eriksson AR. The long-term
efficacy of currently used dental implants: a review and proposed criteria
of success. The International Journal of Oral and Maxillofacial Implants.
1986; 1: 11-25.
221.
el Deeb M, Roszkowski M, el Deeb ME. Nonporous hydroxylapatite
granules as an extracranial and extranasal augmenting material in dogs:
technique and initial findings. Cleft Palate Journal. 1987; 24: 304-313.
222.
Holmström H, Kahnberg KE, Lessard L. The use of preformed HTR
polymer
implants
for
chin
augmentation.
A
preliminary
report.
Scandinavian Journal of Plastic & Reconstructive Surgery & Hand
Surgery. 1993; 27: 109-112.
223.
Kent JN, Zide MF. Wound healing: bone and biomaterials. Otolaryngologic
Clinics of North America. 1984; 17: 273-319.
224.
Schultz RC. Reconstruction of facial deformities with alloplastic material.
Annals of Plastic Surgery. 1981; 7: 434-446.
127
225.
Whear NM, Cousley RR, Liew C, Henderson D. Post-operative infection of
Proplast facial implants. British Journal of Oral & Maxillofacial Surgery.
1993; 31: 292-295.
226.
Gosain AK. Biomaterials in facial reconstruction. Operative Techniques in
Plastic and Reconstructive Surgery. 2003; 9: 23-30.
227.
Moreira-Gonzalez A, Jackson IT, Miyawaki T, Barakat K, DiNick V. Clinical
outcome in cranioplasty: critical review in long-term follow-up. The Journal
of Craniofacial Surgery. 2003; 14: 144-153.
228.
Verret DJ, Ducic Y, Oxford L, Smith J. Hydroxyapatite cement in
craniofacial reconstruction. Otolaryngology - Head & Neck Surgery. 2005;
133: 897-899.
229.
Wiltfang J, Kessler P, Buchfelder M, Merten HA, Neukam FW, Rupprecht
S. Reconstruction of skull bone defects using the hydroxyapatite cement
with calvarial split transplants. Journal of Oral & Maxillofacial Surgery.
2004; 62: 29-35.
230.
Poetker DM, Pytynia KB, Meyer GA, Wackym PA. Complication rate of
transtemporal hydroxyapatite cement cranioplasties: a case series review
of 76 cranioplasties. Otology and Neurotology. 2004; 25: 604-609.
231.
Matsuno A, Tanaka H, Iwamuro H, Takanashi S, Miyawaki S, Nakashima
M, Nakaguchi H, Nagashima T. Analyses of the factors influencing bone
graft infection after delayed cranioplasty. Acta Neurochirurgica. 2006; 148:
535-540; discussion 540.
232.
Shumrick KA, Smith CP. The use of cancellous bone for frontal sinus
obliteration and reconstruction of frontal bony defects. Archives of
Otolaryngology -- Head & Neck Surgery. 1994; 120: 1003-1009.
128
233.
Weber R, Draf W, Kahle G, Kind M. Obliteration of the frontal sinus--state
of the art and reflections on new materials. Rhinology. 1999; 37: 1-15.
234.
Ramay HRR, Zhang M. Biphasic calcium phosphate nanocomposite
porous scaffolds for load-bearing bone tissue engineering. Biomaterials.
2004; 25: 5171-5180.
235.
Bonfield W. Elasticity and viscoelasticity of cortical bone. In: Hastings GW,
Ducheyne P, editors. Natural and living biomaterials. Boca Raton, Florida:
CRC Press; 1984: 43-60.
236.
Motoki DS, Mulliken JB. The healing of bone and cartilage. Clinics in
Plastic Surgery. 1990; 17: 527-544.
237.
Phillips JH, Rahn BA. Fixation effects on membranous and endochondral
onlay bone-graft resorption. Plastic & Reconstructive Surgery. 1988; 82:
872-877.
238.
Sullivan PK, Rosenstein DA, Holmes RE, Craig D, Manson PN. Bone-graft
reconstruction of the monkey orbital floor with iliac grafts and titanium
mesh plates: a histometric study. Plastic & Reconstructive Surgery. 1993;
91: 769-775; discussion 776-767.
239.
Habal MB. Perspectives on what's new in plastic surgery. The new
millennium. Clinics in Plastic Surgery. 1996; 23: 1-2.
240.
Kadiyala S, Jaiswal N, Bruder SP. Culture-expanded bone marrow-derived
mesenchymal stem cells can regenerate a critical-sized segmental bone
defect. Tissue Engineering. 1997; 3: 173-185.
241.
Petite H, Kacem K, Triffitt JT. Adhesion, growth and differentiation of
human bone marrow stromal cells on non-porous calcium carbonate and
129
plastic substrata: effects of dexamethasone and 1,25dihydroxyvitamin D3.
Journal of Materials Science: Materials in Medicine. 1996; 7: 665-671.
242.
Yoshikawa T, Ohgushi H, Uemura T, Nakajima H, Ichijima K, Tamai S,
Tateisi T. Human marrow cells-derived cultured bone in porous ceramics.
Bio-Medical Materials & Engineering. 1998; 8: 311-320.
243.
Yoshikawa T, Ohgushi H. Autogenous cultured bone graft--bone
reconstruction using tissue engineering approach. Annales Chirurgiae et
Gynaecologiae. 1999; 88: 186-192.
244.
Yoshikawa T, Ohgushi H, Nakajima H, Yamada E, Ichijima K, Tamai S,
Ohta T. In vivo osteogenic durability of cultured bone in porous ceramics:
a novel method for autogenous bone graft substitution. Transplantation.
2000; 69: 128-134.
245.
Bioglass. Wikipedia, The Free Encyclopedia. July 23, 2012. 13:59 UTC.
Available
at:
http://en.wikipedia.org/w/index.php?title=Bioglass&oldid=503771225.
Accessed August 6, 2012.
246.
Bronzino JD. The biomedical engineering handbook vol.1. Boca Raton,
Florida: CRC Press. 2000.
247.
Höhland W, Vogel V. Machineable and phosphate glass-ceramics. In:
Hench LL, Wilson J, editors. An introduction to bioceramics. Singapore:
World Scientific; 1993: 125-138.
130