B I O A C TVI EVTEE N
G SL KA AS PS
Bioactive glass:
mechanisms of bone bonding
David C. Greenspan
Bioaktivt glas utvecklades på 1970-
talet som ett syntetiskt material
avsett att användas som bensubsti-
tut vid läkning av patologiska
benkaviteter, t ex vid parodontala
och periapikala bendestruktioner,
benkaviteter efter cystaenukleation.
Förmågan hos materialet att förenas
med ben kunde visas vara relaterad
till bildandet av ett skikt av hydroxi-
karbonatapatit (HCA) på glasets
yta; en bioaktiv bindning (bonding)
till benkavitetens yta etableras.
När materialet placeras i en
fysiologisk miljö, antingen in vivo
eller in vitro, inträffar en serie
ytreaktioner som resulterar i att
joner från glaset frigörs. Detta anses
ske snabbare på ytan av bioaktivt
glas än hos något annat biokera-
miskt material.
I denna översiktsartikel presente-
ras utvecklingen av ett bioaktivt glas
vars möjliga indikationsområden,
t ex i patologiskt fördjupade par-
odontala benfickor, illustreras
genom några nyligen redovisade
kliniska studier av Bioglass® och
PerioGlas®.
tandläkartidningen årg 91 nr 8 1999
T
he use of bioactive glass materials as
implants is relatively new, having been
developed within the past 25 years. Until
the late 1960’s, the goal of biomaterials
development was the creation of materials as
chemically inert as possible [1]. It was only by
minimising the materials’ interaction with the
host that biocompatibility and long-term survival
of implants was achieved. Materials used at this
time were mainly metallic and subject to
corrosion and eventual failure due to the highly
corrosive nature of body fluids. This caused the
search for materials, which were better able to
withstand the chemical attack of the body. Other
implant materials, though non-reactive, were
recognised by the body as foreign and sequestered
by a capsule of fibrous tissue, which led to implant
failure as well.
In the late 1960’s and early 1970’s, the search
for better biocompatiblity of implant materials
resulted in a new concept, namely bioceramic
materials, which would mimic natural bone tissue
[2, 3]. Because hydroxyapatite (HA) is a naturally
occurring ceramic mineral, as well as the mineral
Author
component of bone, it was believed that by David C.
Greenspan, PhD
making synthetic HA for bone replacement the
material would be completely compatible with the in Materials
body. At the same time, Hench [4, 5] developed Science, Chief
Technology
the concept of using a silicate-based material with
Officer, USBio-
calcium and phosphate in proportions identical to
materials
natural bone as an implant material. It was found
Corporation,
that after implantation in bone tissue, these glass
Alachua,
materials resisted removal from the implant site Florida, USA.
and were, in effect, “bonded to bone”.
The composition of the first bioactive glass
invented and tested by Professor Hench is given in Key words
Table 1 [1]. Hench used the term “bioactive glass” Bioactive; bone;
to describe this interfacial bond which developed bonding;
between the implant and host tissue. The term implants.
“bioactive” was later applied to the synthetic HA
materials to encompass the field of biomaterials Accepted for
science known as “bioactive ceramics”. A bio- publication
active material is thus defined as: ‘ a material that May 10, 1999.
G R E E N S P A N

elicits a specific biological response at the interface of sodium ions (Na+) from the surface of the glass
of the material, which results in the formation of a via ion exchange with hydrogen (H+ or H3O+).
bond between the tissues and the material’[6] . This reaction occurs very rapidly, within minutes
The one common feature of these materials is the of exposure to body fluids, and creates a deal-
formation of a hydroxycarbonate apatite (HCA) kalisation of the surface layer with a net negative
surface layer, which was first described by Hench surface charge. During the first minutes of
[1] and later by Davies [7]. exposure of a bioactive glass to an aqueous
environment, the loss of sodium causes a localised
breakdown of the silica network with the resultant
Bioactive glass surface reactivity formation of Si(OH)4 groups, which then repoly-
The unique surface reactivity of bioactive glasses merise into the silica-rich surface layer. This
has been described extensively by Hench [2, 5, 6] surface is highly porous on a microscopic scale,
and others [8–10]. Table 2 summarises the various with an average pore diameter of the order of 30 to
surface reactions which occur at the bioactive glass 50 Å and an effective surface area of up to 100 m2/g.
tissue surface. Stages 1 to 5 occur ostensibly in Following the formation of the silica-rich layer,
sequence. The first step in the reaction is the loss an amorphous calcium phosphate layer will form
on the glass surface and will incorporate the
biological moieties, such as blood proteins,
Table 1. The material composition of 45S5 growth factors and collagen, onto its surface (step
Bioglass® 6). Step 6, the adsorption of organic species from
body fluids, occurs concurrently with the first four
Compound Percentage reaction stages, and is believed to be at least
(wt.%) partially responsible for the biological nature of
the HCA layer. Within about 3 to 6 hours in vitro
SiO2 45.0 [6] this calcium phosphate layer will crystallise
CaO 24.5 into the hydroxycarbonate apatite layer, which has
Na2O 24.5 been described as the bonding layer. Since this
P2O5 6.0 surface is chemically and structurally nearly
identical to natural bone mineral, it allows for the
body’s tissues to attach directly to the surface. As
the reactivity continues, this surface HCA layer
Table 2. Bioglass® reaction stages with increasing time grows in thickness to form a bonding zone of up to
100 micron. The thickness of this HCA layer
Increasing Stage Reaction event forms a mechanically compliant interface that is
time essential for maintaining the bioactive bonding of
the implant to the natural tissue.
▲ 11 Crystallisation of matrix The surface reactions described above occur
within the first 12 to 24 hours after implantation.
10 Cellular attachment
By the time osteogenic cells, such as osteoblasts or
9 Differentiation of stem cells mesynchemical stem cells, infiltrate the bony
defect, which normally takes 24 to 72 hours, they
8 Attachment of stem cells
will “see” a bone-like surface, complete with
7 Action of macrophages organic components, and not a foreign material.
The release of ionic components from the glass
6 Adsorption of biological
surface has been shown to continue for long
moieties (proteins, etc)
periods of time, which enhances the development
5 Nucleation and crystallisation of of the surface reactive layers. It is this sequence of
calcium phosphate to HCA events, in which the bioactive glass participates in
the repair process that allows for the creation of a
4 Precipitation of amorphous
calcium phosphate direct bond of the material to tissue.
Hench has proposed that the loss of soluble
2–3 Dissolution and repolymer- silica from the surface of bioactive glasses might be
isation of surface silica at least partially responsible for the stimulation
1 Sodium hydrogen ion exchange and proliferation of bone-forming cells in the area
Log t
of adjacent to the glass surface [11]. Early work by
0 Initial glass surface Carlisle et al [12,13] in chicks indicates that silicon
plays both a metabolic role in connective tissue at

tandläkartidningen årg 91 nr 8 1999


a cellular level as well as a structural role where
silicon is chemically combined in the ground
substance that surrounds collagen and cells.
Keeting et al. [14] performed studies on human
osteoblast-like (hOB) cells and identified a
potential metabolic function served by soluble
silicon obtained from extracts of zeolite. They
showed a dose-dependent effect of soluble silicon
on the rate of increased DNA synthesis in cell
culture and a threefold increase in mitosis of the
cells when exposed to the soluble silicon.
The body’s normal healing and regeneration
processes (steps 7–11) begin after these surface
layers have begun to form. As has been previously
reported, bioactive glasses appear to minimise the
persistence of the macrophage and inflammatory
responses, which accompany any trauma, in-
cluding surgery [5, 6, 11, 21]. Thus, steps 8 to 11 in
Table 2 can occur more rapidly than has been seen
with implantation of other synthetic materials.
Bone bonding in vivo and in clinical use
The first clinical use of bioactive glass was the 45S5
composition, called Bioglass® (USBiomaterials
Corporation, Alachua, FL, USA), for the recon-
struction of the bony ossicular chain of the middle
ear to treat conductive hearing loss. Details of the
diseased state are beyond the scope of this pre-
sentation, but a review of clinical needs and
materials for ossicular chain reconstruction and
their performance has been published elsewhere
[15, 17]. Until bioactive glasses for ossicular re-
placement was attempted, the long-term prog-
nosis for surgical success was not very good. A
bioactive glass-ceramic, Ceravital® (Schott Glass,
Germany) was introduced in 1981 and the early
clinical results published in 1984 [15]. These early
results were clearly better than those of the
polymeric or metallic prostheses used at that time.
In 1982, Merwin et al. [17] reported the use of
Bioglass® to reconstruct the ossicles. In that study,
it was discovered that the bioactive glass bonded
not only with the remaining bone stock of the
ossicle, but also directly to the tympanic
membrane via collagen attachment to the surface
of the glass. This was the first time any implant
material demonstrated direct bonding to the soft
tissue of the tympanic membrane. As has been
reported by Hench [11] only bioactive glasses,
which exhibit high rates of surface reactivity,
demonstrate the ability to bond with soft tissue.
The glass compositions listed in Table 3 as Class
‘A’ bioactivity have this soft tissue bonding ability.
In a retrospective analysis with a 10-year
follow-up of clinical studies, Lobel [15] found that
the overall success rate for the Bioglass® and
tandläkartidningen årg 91 nr 8 1999
B I O A C T I V E G L A S S
Ceravital® implants was significantly greater than
for the polymer systems. Extrusion rates for these
materials were only 3% and 9%, respectively,
compared to rates from 23% to 60% for various
polymer systems.
Another early clinical use of a bioactive glass
composition was developed by a research team
headed by H Stanley [18, 19], using the 45S5
composition of Bioglass® shown in Table 1 as a
natural tooth form implant after extraction.
During the initial phases of these studies, it was
found that after splinting the tooth for 3 months,
all implants were retained solidly in the sites,
evidently bonded to the bony tissue. After 6
months, however, it was discovered that the
implants were missing and the sockets healed
over. Upon histological examination of these
implant sites, the root portion of the original
implants remained in the dental ridge directly
bonded to bone.
This discovery led to the development of a
totally submerged ridge maintenance implant to
preserve the alveolar ridge following tooth
extraction [20]. The bioactive glass cones acted as
space fillers after the extraction of natural teeth,
and delayed the resorption of the alveolar ridge.
The long-term clinical report of a human study of
242 implants showed an overall success rate of
86% with an average follow-up of 5 years [21]. In
the study, the patients followed for the longest
period of time were followed for 9 years 3 months
after surgery. These results were significantly
better than those of the previous clinical trials with
similar root form implants made from dense
hydroxyapatite, where the rate of implant loss and
dehiscence (gradual migration of the implant
through the gingiva) ranged from 10% loss and
13% dehiscence [22] to over 50% implant loss
[23]. It has been postulated that the main reason
Table 3. Bioactive glass composition ranges (in wt.%)
Class ‘A’ bioactivity Class ‘B’ bioactivity
(wt. %) (wt. %)
SiO2 42–50 52–58
Na2O 14–28 3–20
CaO 12–26 8–20
P2O5 3–9 3–12
Al2O3 0–1 0–3
MgO 0–3 0–12
K2O 0–6 0–12
CaF2 0–12 0–18
G R E E N S P A N
for the higher success rate of the bioactive glass
implants is the more rapid formation and greater
degree of formation of the bioactive HCA layer at
the surface of the implants, which acts as a
pseudo-periodontal ligament.
While the initial clinical application of bulk
bioactive glass implants was successful, this
limitation of poor mechanical strength resulted in
the development of applications as particulates for
filling bone voids. In these non-structural graft
sites, load bearing was not a requirement. The first
successful use of bioactive glass for filling bony
defects was reported by Wilson in a primate model
in 1986 [24]. It was found that the bioactive
glass granules not only allowed bone to fill into
the periodontal defects, but encouraged the prolif-
eration of bone throughout the defect simul-
taneously, i.e. bone growth independent of
connection with the bony wall of the defect. This
was termed “osteoproduction” and clearly dis-
tinguished bioactive glass from osteoconductive
materials, such as hydroxyapatite.
This study also showed that Class ‘A’ bioactive
glass produced much more bone fill in the defect
than did hydroxyapatite materials. Histological
results from the study demonstrated that the
Bioglass®-filled defects inhibited the downgrowth
of epithelial tissue as well as epithelial attachment
close to the implantation level. These results were
not seen with the hydroxyapatite and tri-calcium
phosphate materials studied. The authors deter-
mined that this represented a restoration of both
alveolar bone and periodontal ligament.
One of the drawbacks of that early study was
that the defects were surgically created. A more
recent study using the 45S5 Bioglass® compo-
sition, reported by Karatzas et al. [25] used adult
Rhesus monkeys with chronic periodontal defects
created by using orthodontic bands and silk
ligatures. The results at 4 and 8 weeks showed
significantly more new cementum in the bioactive
glass-grafted sites and less epithelial downgrowth
than the unfilled controls. In addition, the authors
noted what appeared to be new attachment with
the appearance of Sharpey´s fibres around the
cemento-enamel junction. The authors also re-
ported new bone formation as early as 4 weeks in
the bioactive-grafted sites.
The first reported use of Bioglass® in a human
periodontal defect was by Froum [26]. In a con-
trolled, blinded study comparing Bioglass® par-
ticulate (trade name PerioGlas®, USBiomaterials,
Alachua, FL, USA) with debridement, the author
reported a significantly greater reduction in
probing pocket depth in the PerioGlas®-grafted
sites, 4.26 mm reduction, than in the control sites,
3.44 mm. In addition, the osseous fill, as measured
by re-entry at 12 months, was significantly greater
for the PerioGlas®-grafted sites, 3.28 mm (62.0%),
compared to the control sites, 1.45 mm (33.6%).
This demonstration of bone fill confirmed the
animal findings in earlier studies.
Another study, published by Fox [28], using
a bioactive glass identical in composition to
PerioGlas®, reported results, which were similar
to those of Froum et al [26, 27]. A more recent
study, published by Low et al. [29], showed bone
fill, as measured by subtraction radiography, and
reduction in probing pocket depth to be quite
similar to that reported by Froum. Although the
patient group was small (12 patients and 17
treated defects), a probing pocket depth reduction
of 3.33 mm at the 2-year follow-up was reported,
as well as a bone fill of 3.47 mm. The Low study
[28] also compared results at 1 year and 2 years in
the treatment group and found that the clinical
results had remained stable during that time
period. A report by Shapoff et al [30] of over 200
periodontal cases in his private practice showed an
average clinical reduction in probing pocket depth
of about 53%. These results are also quite similar
to those reported by the other authors in the
above-mentioned controlled clinical studies.
Although the studies cited above comprised
relatively small numbers of subjects, and varied in
case selection, duration and to some extent in the
methods of analysis of the outcomes, there are
striking similarities amongst them. The average
reduction in probing pocket depth of the bioactive
glass-grafted sites varied, on average, from about
53% to 64%; probing attachment gain was about
2.00 mm to 3.00 mm and bone fill was around
60% to 65%. When compared with unfilled con-
trols, these results were always statistically signifi-
cant. In all cases, the response of the soft tissue to
the graft material was excellent, which may be due
to the reported ability of this material to bond
with soft tissue.
Summary
The technology of bioactive glasses for medical
use is relatively new. To date, there have only been
a few clinical uses of these materials, but during
the 13-year clinical history, these materials have
been extremely successful. Perhaps most telling in
their use is the fact that there has been no report of
any adverse response to these materials in the
body.
It has been postulated that the release of soluble
silica from the surface reactions of these glasses,
combined with the formation of the HCA layers,
actually stimulates and accelerates bone healing.
Research to prove or disprove this hypothesis is
tandläkartidningen årg 91 nr 8 1999

being conducted at numerous university and
industrial laboratories throughout the world, and
there is a growing body of evidence that suggests
that Class ‘A’ bioactive glasses do stimulate the
repair and regeneration of bone and connective
soft tissue.
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Conference continuing education lecture at the
Scandinavian Society of Periodontology Annual
Meeting in Kolmården, Sweden, 8–10 May, 1998.
This lecture was presented by Dr DC Greenspan,
also Vice President of the USBiomaterials Corpo-
ration, FL, USA.
Address
David C Greenspan, US Biomaterials Corporation,
One Progress Boulevard , # 23, Alachua, FL 32615,
USA.