Biomed.

Glasses 2019; 5:178–184

Review Article

David Greenspan*

Bioglass at 50 – A look at Larry Hench’s legacy

and bioactive materials
https://doi.org/10.1515/bglass-2019-0014 in part on the theory that by making materials less reactive,
Received Nov 25, 2019; revised Dec 08, 2019; accepted Dec 09, 2019 the inflammatory response and hence ‘rejection’ of the im-
plant material would be lessened, resulting in a more suc-
Abstract: In 1969, fifty years ago, a young professor of
cessful device. A survey of the literature at that time sup-
ceramic engineering created a 4-component glass to be
ports this point [2–5]. In the late 1960’s and early 1970’s bio-
used as a bone replacement material. That material be-
materials research was focused on blood compatible sur-
came known as “Bioglass” and more generally as a class
faces, metals with minimal reactivity in the body, some ce-
of materials known as bioactive glass. Those first exper-
ramic bone graft materials and polymers that would not
iments conducted by Dr. Larry Hench completely shifted
elicit an intense inflammatory response, but there was no
the paradigm of how the biomaterials and medical com-
concept about material-tissue bonding. It was beyond the
munities look at the interactions between inorganic mate-
realm of possibility at that time that a synthetic material
rials and tissues in the body. This article will touch on just
could have a positive impact on tissue healing (later ex-
a few highlights of the development of bioactive glasses
panded to tissue regeneration) and have an ability to form
and relate those to the concepts of bioactivity and tissue
a bond with the repairing tissue.
bonding.
The first studies conducted by Professor Hench were
Keywords: bioactive glass, bioactivity, hydroxy apatite, all directed towards repair of bone tissue since that was
Hench, tissue regeneration an area within the medical device community that was
growing rapidly. The initial publications of the results of
those early experiments with Bioglass were initially met
with some curiosity and even skepticism in the early 1970’s.
1 The early years
While those early publications from Professor Hench’s
group verified that some kind of direct attachment be-
The story about how Professor Hench came to be inspired
tween bone and the glass implant had occurred, the mech-
to switch his focus from researching radiation damage in
anisms could not be easily explained and a rigorous theory
glass for space-based applications and the dielectric prop-
about how this phenomenon took place had not yet been
erties of glass and glass-ceramics to biomaterials has been
developed [6–9].
told in numerous publications, so those details won’t be
During the early years of development of various
repeated here. Perhaps the best and most interesting ac-
bioactive glass and glass-ceramic materials, Professor
count is Dr. Hench’s article in 2006, “The story of Bioglass”,
Hench published a number of articles on the surface reac-
and it is worth reading to gain an overview of some of the
tions of these bioactive glasses. Many of the salient publi-
details of the development of this class of biomaterials [1].
cations are described in “The story of Bioglass” by Hench,
While the invention of bioactive glass has resulted in sig-
referenced above. The observations of the interface be-
nificant commercial success in some applications, what
tween tissue and material in simple monolithic bone im-
is salient and perhaps most important is how that inven-
plants in either rats or rabbits were then compared with
tion and the unique surface properties of a limited series
the in vitro data to gain a better understanding of the reac-
of glass compositions has created an entire field of study;
tions and sequence of those reactions leading to this bond-
namely bioactive materials.
ing interface. Much of the detail of these early works are
At the time that Professor Hench created the first bioac-
captured in a series of 9 reports to the U.S. Army Medical
tive glass compositions, the majority of research was based
Research and Development Command which funded the
initial work and continued to fund Professor Hench’s pro-
gram for 9 years [9]. While it is beyond the scope of this
*Corresponding Author: David Greenspan: Spinode Consulting
article to go into details of those early works, it is inter-
St Augustine, United States of America;
Email: dspinode@gmail.com esting to note that the first compositions tested included

Open Access. © 2019 D. Greenspan, published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0
License
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 Bioglass at 50 – A look at Larry Hench’s legacy and bioactive materials
crystallized compositions, including the original ‘45S5’
(45 wt% SiO2, 24.5 wt% Na2O, 24.5 wt% CaO and 6 wt%
P2 O5 ) composition as a glass-ceramic. The hypothesis was
that a glass-ceramic material would have the mechanical
strength to support load bearing applications. Once the
chemical bond with bone was demonstrated in those first
studies it was further postulated the crystalline structure
of the glass-ceramic, coupled with the surface reactivity of
the glass-ceramic enhanced and was responsible for the
precipitation of the calcium phosphate layer [10].
When scanning the literature today, the original,
iconic ‘45S5’ composition is still often referenced. What
has been lost to much of the history is that the first 4 to
5 years of research looked at a wide range of silicate com-
positions, including, different levels of silica as the net-
work former, additions of boron and fluoride to modify
melting temperature for flame spraying coatings, as well
as the comparison of amorphous versus crystallized com-
positions [9, 10]. Because these U.S. Army Reports were
not widely circulated, nor peer-reviewed, much of that
early work that helped shape the direction of research with
bioactive glass and theory of bone bonding has never been
seen by the biomaterials community.
However, as more researchers began to study these
materials, by 1980 there was a slow acceptance by the bio-
materials community of the premise that an inorganic, syn-
thetic material could directly attach to bone tissue with-
out an interposing fibrous layer. This acceptance led re-
searchers to look at a wide range of materials that might
bond to bone.
2 Bioglass, surface reactivity and
the term “bioactivity”
The first use of the term “bioglass” occurs in the second
U.S. Army Report. That term appears in the summary of
accomplishments and the exact term was written as “bio-
glass- ceramic” [10]. It is important to note that the first use
of this word included the term “ceramic”. The initial thrust
of Professor Hench’s research was to use a glass-ceramic
material for bone replacement as he believed that these
crystallized compositions would be strong enough to be
load bearing, so many of the early peer reviewed publica-
tions were of Bioglass-ceramic constructs as well as amor-
phous glass samples. Over the next few years, the term be-
came used more frequently for both amorphous and crys-
talline compositions, and in 1976 the word “Bioglassr ”
was actually trademarked by the University of Florida.
| 179
It is not clear when the first use of the term ‘bioac-
tive glass’ appeared in the literature, or the term ‘bioactiv-
ity’, but by 1982, in a publication by Hulbert, Hench, For-
bers and Bowman, a definition for a ‘bioactive material’ ap-
peared. The definition is as follows: “A bioactive material
is one that elicits a specific biological response at the inter-
face of the material that results in the formation of a bond
between tissues and the material” [11]. In time, this defini-
tion became the definition of ‘bioactivity’ as it relates to
glass and other biomaterials used as implant materials.
In 1976, a publication by Clark, Hench and Paschall de-
scribed the multi-layer interfacial zones that form between
the original glass surface and bone tissue [12]. In this pub-
lication, the authors laid out the basic sequence of events
that occur following implantation, based on both in vivo
histological results and in vitro reaction studies of multi-
ple glass compositions. The authors describe a dynamic
surface chemistry that is dependent on glass composition
in both hard and soft tissue. This was the first attempt to
create a fully operational theory of the mechanism of tis-
sue bonding. As interest in the concept of bone-bonding
and tissue attachment grew through the late 1970’s and
into the early 1980’s, the pace of research in the bioma-
terials community quickened. Research efforts included
new compositions of glass, new applications and a more
in-depth understanding about how the reactivity of these
materials affected their performance. In fact, the basic
premises laid out in that 1976 publication were validated
through the research of investigators around the world
who were looking at a myriad of new biomaterials.
Following from the theory of the influence of surface
chemistry of bioactive glass on the interface with bone,
Professor Hench continued to refine his approach and by
the early 1980’s had published the now well accepted and
often used ‘reaction sequence’ that occurs when bioactive
glass is implanted in bone or soft tissue. While there are
many different forms of this figure that have been pub-
lished, Figure 1 represents the first steps in the reaction se-
quence that leads to the formation of a crystalline hydroxyl
carbonate apatite (HCA) layer. This layer was described as
the bonding layer; Hench stated that for a bond with tissue
to occur a layer of biologically active HCA must form [13].
This theory was tested often and by many researchers, and
by 1990 this was accepted by most as the mechanism of
bone bonding [14].
Today, one of the first attributes to be tested for new
bioactive materials, or modifications of existing materials
is whether an HCA layer will form on the surface. In fact,
in many publications, the formation of an HCA layer is
used as a surrogate for making the claim that a material is
bioactive. The biomaterials community has promulgated,
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180 | D. Greenspan
Figure 1: An early version of the Reaction Stages of Bioglass as
postulated by Professor Hench (courtesy of Prof. Julian Jones).
Figure 2: Diagram showing compositional dependence of bone-
bonding and soft-tissue bonding of bioactive glasses. Professor
Hench had designated compositions that bond with both bone
and soft tissue as Class A bioactive glasses, and those that only
bond with bone as Class B bioactive glasses (diagram courtesy of
Professor Julian Jones).
through the International Organization for Standardiza-
tion (ISO), a standard in vitro test method determining the
apatite forming ability of an implant material (ISO 22317)
[15]. In this test method there is a description and defi-
nition of bioactivity, and although the standard does not
purport to equate the HCA forming ability of a material to
its bioactivity, that link is commonly made today. In fact,
much of this linkage is owed to the often used and refer-
enced compositional triangle of bioactive glass composi-
tions and regions of both bone and soft tissue bonding pro-
duced by Professor Hench, and one such iteration is shown
in Figure 2. This diagram was created over a period of 10
to 15 years by adding data from numerous experiments,
not only by Hench but many others as well [16]. In many
descriptions of this figure, Hench describes the range of
bioactivity of the various compositions within the different
regions of that compositional triangle.
While Figure 1 lays out the reaction sequence as it is
envisioned from mainly laboratory in vitro solution reac-
tivity studies, what is missing from the reaction sequence
is the fact that the organic elements in the body will start
to react instantaneously with the surface of any material.
Professor Hench updated this figure in the mid 1990’s to
include the biological events that occur at the surface of
the glass, but these events still appear in the figure after
the surface reactivity has resulted in the formation of an
apatite layer [17]. Thus, while that diagram is a simple way
of explaining how silicate bioactive glasses behave in so-
lution, it does not at all convey a complete story of the be-
havior of these materials in vivo, nor does it explain the
very positive attributes that these materials have shown in
commercial use.
3 HCA layer and bioactivity: a
result of surface reactivity or
mechanism of tissue bonding?
While the concepts of bioactivity and tissue bonding and
the HCA layer have become ubiquitous and accepted in
the biomaterials community today, it is not clear that the
story is that simple. In fact, a rabbit study published in
1997 showed that a bioactive glass particulate (45S5) im-
planted in the distal femur, produced bone regeneration of
the defect much more rapidly and completely than a dense
hydroxy apatite particulate [18]. From these results, it was
clear to Professor Hench that the bone bonding and very
rapid regeneration of tissue for the bioactive glass had to
be at least partly due to the ionic release from the glass.
This revelation set Professor Hench on to study how the
ions released from bioactive glass affected osteoblasts and
stem cells. In a series of publications beginning around
2000, Hench and others demonstrated that the stimula-
tory effect on bone cells was due, at least in part, to ions
released from the glass [19–21]. In a number of these stud-
ies, the bioactive glass, usually the 45S5 composition, was
reacted in cell culture medium, removed after a period of
time, and that media replaced media in which various cell
types were growing. Thus, a standard cell culture media
was supplemented with ionic reaction products from the
bioactive glass. In all cases, this additional ionic concen-
tration led to stimulation of cellular activity. It was from
these first studies that the conclusion was drawn that in
addition to the HCA layer, the ionic release was critical to
the stimulatory effect and rapid tissue repair ascribed to
bioactive glasses.
Today, researchers have determined that certain bioac-
tive glasses can stimulate angiogenesis and that there is
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 Bioglass at 50 – A look at Larry Hench’s legacy and bioactive materials | 181

a dose response, suggesting that it is ionic release that composition of the glass, although these efforts were not
is responsible for this effect. Day performed cell culture rigorous enough to be statistically definitive [32, 33].
studies using a transwell system where bioactive glass par- For the titanium dental implants however, the osseoin-
ticulates were exposed to the cell culture media, but not tegration could be measured by survivability of actual den-
in contact with the cells [22]. A review of angiogenesis in tal implants as a function of surface treatment [34]. Thus,
bioactive glasses confirmed the effects both in vitro and in the term osseointegration, when used to rank materials
vivo [23]. These results confirmed the initial studies of this or surfaces, can be more quantitative than the term bioac-
type performed by Professor Hench. Others have shown tivity used for bioactive glasses. For the term bioactivity,
that bioactive glass possesses an anti-microbial activity, the fact that the speed at which an HCA layer forms on
also ascribed to the release of ions from the glass [24, 25]. the surface of a given bioactive glass is often used to con-
From these and other results it is not clear that one can sim- vey a more ‘bioactive’ and therefore potentially better im-
ply draw a direct correlation between the formation of an plant material, is perhaps a leap too far since the defini-
HCA layer and the bioactivity of any bioactive glass. tion of bioactivity that is accepted depends on a biologi-
Throughout this manuscript, the terms bioactive glass, cal response to a material that results in a bond with tis-
bioactivity and bioglass have sometimes been used inter- sue. Somehow, that bond must be measured if one is to
changeably. But ‘bioactivity’ is not solely related to this use bioactivity as a quantitative value.
class of materials. Titanium implants, long a standard in
dental implantology have always described their positive
attributes with bone tissue as osseointegration. Osseointe-
gration has been defined as the direct structural and func-
4 Commercial status of bioactive
tional connection between living bone and the surface of glass and concluding remarks
a load-bearing artificial implant [26]. Titanium alloys have
also been long used in hip and knee prostheses as well as Fifty years after the first animal experiment with the orig-
in other orthopedic hardware. In the late 1990’s, titanium inal bioactive glass composition (45S), the field of bioac-
alloys were introduced as spinal fusion cages. tive glasses is robust and has seen significant commercial
With the rapid growth of spinal fusion cages or spac- utility. The main applications of this material for medi-
ers, a significant amount of research has been conducted cal devices cleared for market through the various regu-
on the osseointegration of these devices with bone. Re- latory schemes include particulates for bone regeneration
searchers have shown that surface topography, namely mainly in spine fusion applications, in fibrous forms for
multi-scale roughness has a positive effect on cellular at- use in chronic wound healing as a dressing and as fine
tachment to the titanium alloy surface [27–29]. The realiza- particulates in oral care, mainly as an ingredient in tooth-
tion that specific surface features can affect osseointegra- paste to treat dentinal hypersensitity. There are also a num-
tion and cellular behavior has allowed for major advances ber of additional forms and uses of these materials cur-
in the success of these implants. With these efforts more rently in clinical studies in humans. It is beyond the scope
and more research publications have used the term ‘bioac- of this short article to go into the details of these various
tive’ to describe the effect those surface features have on applications, but the reader is directed to two recent and
the osseointegration of the implant with bone as defined quite complete reviews of the field and status of bioactive
by Albrektsson [30, 31]. glasses: one published in 2017 by Montazerian and Zan-
If one takes Albrektssons’ definition of osseointegra- otto, and one published in 2018 by Baino, Hamzehlou and
tion and Hench’s definition of bioactivity one sees that Kargozar [35, 36]. These reviews not only give a more com-
these definitions as written are qualitative and not quan- plete picture of the chronology of developments in the field
titative. Although Hench developed a system of classify- of bioactive glasses, they also trace the commercial devel-
ing bioactive glass compositions with respect to whether opment of these materials.
they would bond with bone and soft tissue or just bone or It is safe to say that the process of getting from an
not at all, these were limited to a range of silicate-based idea for a novel or even just improved material to a fin-
glasses. Greater bioactivity was ascribed to a material that ished medical device allowed for sale is an arduous one.
produced more bone in a defect or that attached to certain The path to commercial success of bioactive glasses, which
types of soft tissue. There were also early attempts in some began in 1985 with the first middle ear prosthesis has not
bone implant configurations to measure the strength of the been simple, nor straightforward, for many business and
bioactive glass-implant interface and compare that to the regulatory reasons which are well beyond the scope of this
article. However, what has always been impressive as one

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182 | D. Greenspan

reviews the commercial landscape is that the use of bioac- With the significant advances in the materials sciences
tive glass in medical devices has rarely been associated and the biological fields these past 15 to 20 years, the vi-
with any significant adverse responses for any given ap- sion of being able to create those patient specific solutions
plication. Certainly, there have been clinical failures and and tissue engineered organs is becoming closer to a re-
if not used properly the materials can result in localized ality. While serious challenges still remain, the pace of
adverse events, but as a class of materials these appear to progress has not slowed and this gives one confidence that
be the most biocompatible materials in the market today. cell seeded scaffolds will become fully integrated as new,
A word of caution is needed, however; safety for materi- natural tissue. These new visions and possibilities bring
als used in medical devices is determined by the safety of new challenges and thus perhaps requires a reset of how
the medical device ultimately used for a given application, one thinks about and describes bioactive materials.
or indication for use. Thus, a material that appears to be It was over forty years ago that Professor Hench coined
very safe in early biocompatibility testing might be incor- the phrase ‘bioactive glass’ and the term ‘bioactivity’.
porated into a device that ultimately is determined to be These terms were strictly limited (at the time) to trying
unsafe for use. to describe features of these materials related to mono-
The ultimate test of any new biomaterial or applica- lithic constructs used to repair bone defects or to be used
tion of a biomaterial is in the human clinical performance as structural bone replacement devices. It is a testament
of the device. This is perhaps the greatest challenge to the to the thought processes that these definitions have re-
advancement of bioactive glasses. Clinical trials are long, mained largely unchanged in the lexicon that biomateri-
difficult to conduct and very expensive to run. In the de- als scientists use today. That said, perhaps it is time to
velopment of any medical device or drug delivery system, re-think the definition of bioactivity as it relates to this
the marketplace often dictates what applications pass the class of materials. Perhaps bioactivity should be more cen-
barrier of rising to the level of supporting clinical trials. tered on how chemistry, surface charge, topography, ionic
With a focus on those elements highlighted in this article release and the local environment control the biological
and the knowledge of surface chemistry, ionic release, im- events that lead to the very positive outcomes that we see
plant surface topography, surface charge and how to de- in many of the research articles published today, and less
termine how those affect cells and tissues it should be pos- on the formation of a bond with tissues.
sible to streamline some of the testing needed to gain ac- Certainly, the works referenced in this article and in
cess to clinical studies. While the HCA layer formation and the extensive review articles have highlighted the fact that
the generic use of the term bioactivity has some value as surface texture, ionic release from bioactive glasses and
descriptive elements, the field should focus on what has surface chemistry are critical to the performance of these
been learned recently about how these other properties of materials. Perhaps the formation of a hydroxyl carbon-
bioactive glasses impact the cellular response and how to ate apatite layer is merely an outcome of these properties,
harness those into advanced applications. rather than a required physical entity that is described as
Bioactive glasses have already received a positive re- the mechanism of bone-bonding. Trying to decipher all
sponse in the market, and the promise of future applica- of the biological queues given when cells are exposed to
tions are much grander in scope and scale than what the bioactive glasses is incredibly complex and perhaps be-
current applications are today. The review papers on bioac- yond our ability currently to completely understand and re-
tive glasses cited above go into some detail about tissue solve. In his last review manuscript on the history of bioac-
engineering applications and scaffolds and different forms tive glasses, published in the inaugural issue of this jour-
and compositions of materials. In 2006, in his article “The nal, Professor Hench laid out a challenge to those work-
story of Bioglass” Hench posits that, “It should be feasi- ing in the field, not to focus on small incremental advance-
ble to design a new generation of gene-activating biomate- ments in the field, but rather to, “. . . strive for unique and
rials tailored for specific patients and disease states.” He innovative approaches at a fundamental molecular biology
goes on to state, “Tissue-engineered constructs based on level to create new bioactive materials. . . ” [37]. While the
a patient’s own cells may be produced that can be used challenge laid out by Professor Hench is certainly a steep
to select an optimal pharmaceutical treatment”. Professor one, it is one worthy of pursuit. It might seem a daunt-
Hench always was a visionary in this field and some of ing task to live up to that challenge, but 25 years ago the
what he stated in that section of the article is becoming thought of completely cataloguing the human genome was
closer to reality and that is a testament not only to the man, regarded by some as onerous, nearly impossible and yet
but to the invention he produced that began this journey today it stands as a great achievement and has facilitated
into what we call bioactive materials. many of the advances of the past decade. In “The story of

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 Bioglass at 50 – A look at Larry Hench’s legacy and bioactive materials |
Biolgass” Professor Hench concluded, “But we need to re-
member that only 35 years ago the concept of a material
that would not be rejected by living tissues also seemed
unimaginable. Bioglass provides a starting point”. That
same sentiment holds true today.
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