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Journal of Structural Biology 163 (2008) 229234
www.elsevier.com/locate/yjsbi

Review

Biomineralization: A structural perspective

Stephen Weiner *
Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Received 18 December 2007; received in revised form 24 January 2008; accepted 1 February 2008
Available online 7 March 2008

Abstract
Biomineralization is an inherently structural subject; the structure of the mineral phase, the structure of the matrix composed of macromolecules and especially the structure of the interphase zone between them. Studies of the dynamics of mineral formation have
revealed that a widespread strategy used by many organisms is to rst form a disordered mineral phase. Only when it is in place and
has adopted its appropriate shape, is it induced to crystallize. Matrix studies have highlighted the importance of a unique group of proteins that are rich in aspartic acid. These are involved in controlling mineral formation. Relating structure to function in mineralized
tissues, often involves an understanding of mechanical properties in terms of not only the hierarchical structure of the tissue, but also
the graded structure that varies from one location to another. Structure is thus in many respects the foundation upon which the eld
of biomineralization rests.
2008 Elsevier Inc. All rights reserved.
Keywords: Biomineralization; Biomaterials; Mineral formation

The eld of biomineralization has its roots in the late

17th century with the advent of the compound microscope.
Mineralized tissues were among the many objects that van
Leeuwenhoek examined with his state-of-the-art microscope. In fact, using a magnication of some 400 times,
he identied the osteons common in many bones (van
Leeuwenhoek, 1693), and Havers identied the lamellae,
even though each lamella turns out to be just 3 or so
microns thick (Havers, 1691). The advances in biomineralization research have tracked the development of tools for
structural studiesrst optical microscopy, then polarized
light microscopy, X-ray diraction, TEM, SEM, and is
now beneting enormously from the advent of cryo-techniques for TEM and SEM.
Biomineralization is a eld that is built on understanding structurethe mineral phase, the many macromolecules that make up the framework in which the minerals
form and in particular the interphase that links the two.
The variety of structures, as well as the diversity of minerals and macromolecules that make up these tissues, is
*

Fax: +972 8 934 4136.

E-mail address: steve.weiner@weizmann.ac.il

1047-8477/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.jsb.2008.02.001

amazing (Arias and Fernandez, 2007; Bauerlein, 2007;

Dove et al., 2003; Lowenstam and Weiner, 1989; Simkiss
and Wilbur, 1989) (Fig. 1). The study of mineral formation
in biology and the products of this process, have produced
many surprises. A few examples recently published in the
Journal of Structural Biology are the remarkably engineered structure of a siliceous sponge (Weaver et al.,
2007), biologically controlled disorder in crystals (Pokroy
et al., 2006) and the incredible hierarchical structure of corals (Cuif and Dauphin, 2005). A big surprise in recent years
was the realization that many animals do not form their
crystals directly from a supersatured solution, but rst produce a transient precursor mineral phase that subsequently
transforms into the mature phase.
We all know that crystals nucleate and grow from a saturated solution. And so they do in vitro, but not necessarily
in vivo. Biology has chosen another pathway; crystals are
grown from an unstable solid colloidal phase, almost
devoid of water. The identication of this unexpected strategy has its origins in a much overlooked paper published in
1967 in the Journal of Ultrastructure Research; the forerunner of the Journal of Structural Biology. Towe and
Lowenstam (1967) showed for the rst time that in the min-

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S. Weiner / Journal of Structural Biology 163 (2008) 229234

Fig. 1. Scanning electron micrographs of 4 dierent mineralized tissues. (a) Statoconia from the bullfrog, composed presumably of aragonite (Marmo
et al., 1983) (Micrograph by H.A. Lowenstam). Scale bar: 1 lm. (b). Aragontic nacre in the process of formation on the inner surface of the bivalve Atrina
rigida. (Micrograph by F. Nudelman). Scale bar: 5 lm. (c). Antler-shaped spicules from the ascidian Pyura sacciformis composed of carbonated apatite
(Lowenstam, 1989) (Micrograph by H.A. Lowenstam). Scale bar: 100 lm. (d). Fracture surface of the working stone part of the sea urchin (Paracentrotus
lividus) tooth. The elongated needles of Mgcalcite are embedded in a matrix of nanoscale crystals composed of calcite with very high concentrations of
Mg (Schroeder et al., 1969; Wang et al., 1997) (Micrograph by Y. Ma). Scale bar: 2 lm.

eralized teeth of the chiton, a segmented mollusk, the initially formed mineral phase is not the same as the mature
form, but transforms into the more stable mature phase.
In order to identify this easily overlooked transient phase,
Towe and Lowenstam (1967) took advantage of the fact
that chitons form their teeth using a conveyor belt-like system, where every row of teeth represents a dierent stage of
formation. They could thus isolate the teeth with initial
mineral deposits and then compare this mineral, with the
mature crystalline phase. They found that the rst mineral
deposited was a disordered hydrated iron oxide, ferrihydrite (Fig. 2), and that within a few days after formation
it transformed into the crystalline iron oxide, magnetite.
In fact the mature teeth are magnetic. Chiton magnetite
was the rst example of biogenic magnetite to be discovered (Lowenstam, 1962).
It took 30 more years for the signicance of this paper to
be appreciated. This occurred when it was demonstrated
that members of another phylum, the echinoderms, also
use this transient precursor phase strategy. Beniash et al.
(1997) showed that sea urchin larvae form their calcitic
spicules via a transient disordered precursor phase called
amorphous calcium carbonate (ACC). The last decade
has witnessed an almost exponential increase in the number

of publications on ACC, (for example, Loste et al., 2003)

and on transient precursor phases in many dierent phyla
(Dillaman et al., 2005; Meibom et al., 2004; Politi et al.,
2006; Weiss et al., 2002). In the last few years, the debate
as to whether vertebrates also form their skeletons via precursor mineral phases (Brown and Chow, 1976; Glimcher,
1984) has been renewed, with some new compelling in vivo
evidence based on Raman spectroscopy (Crane et al., 2006)
and in vitro evidence showing collagen mineralization via
an amorphous calcium phosphate precursor phase (Olszta
et al., 2007). So it turns out that many organisms do not
form their crystals by nucleation and growth from a saturated solution, but they rst produce an unusual disordered
colloidal phase, and then from this the mature crystal is
nucleated and grows. Some of the assumed advantages of
this strategy are that the colloidal phase can be more easily
shaped than a crystalline phase, and that it minimizes the
logistic problem of removing large volumes of water from
the site of mineral formation (Weiner et al., 2005).
The site of formation of the precursor phase is not well
known. In the chiton tooth studied by Towe and Lowenstam (1967) it appears to be the ferritin containing vesicles
inside the epithelial cells responsible for tooth formation.
In the sea urchin larva it also appears to be within vesicles

S. Weiner / Journal of Structural Biology 163 (2008) 229234

Fig. 2. Original micrograph of incipient mineral deposition on the brous

organic meshwork (OsO4 xation, unstained) (Magnication:130,000;
scale bar 0.1 lm). Inset shows a particle made up of an smaller crystallites
(Magnication 350,000). From Towe and Lowenstam (1967).

inside the cells responsible for spicule formation (Beniash

et al., 1999). The source of ions for mineral formation is
via the food the organism eats, or directly from the environment; sea water in the case of marine organisms. It
has indeed been demonstrated that in the case of foraminifera, droplets of sea water are directly imbibed and used as
the source of ions for their calcitic shells (Erez, 2003). The
high Mg/Ca ratio of sea water would promote the formation of amorphous calcium carbonate as the water is
removed (Loste et al., 2003; Raz et al., 2000). Much more
attention needs to be paid to the intracellular environment
in terms of mineral formation.
This change of paradigms in the eld of biomineralization has opened up many fascinating structural questions.
The precursor phases are not amorphous in the sense that
all the atoms are totally disordered. In fact, even the precursor phases already have the short range order of the
mature phase into which they will crystallizein the case
of ACC, aragonite (Marxen et al., 2003) or calcite (Politi
et al., 2006). Another surprise is that the crystalline mature
phase is also slightly disordered when compared to its nonbiological counterpart. In fact it still preserves a memory
of the manner in which it formed (Gueta, 2003). How all
this is achieved, is still a mystery. Solving this mystery
involves focusing not on the atomic order of crystals, but
on the disorder, and thus involves the use of a wide range
of techniques for the characterization of less ordered

231

phasesEXAFS, X-PEEM, infrared spectroscopy, Raman

spectroscopy, DTA-TGA and more. The concepts most
appropriate for understanding the processes involved in
tracking the transformation from a disordered to an
ordered phase, are those related to crystallization from a
high temperature melt rather than from a saturated solution at ambient temperatures (Olszta et al., 2007). Biology
has indeed produced a major surprise when it comes to
mineral formation.
Each mineralized tissue contains tens of dierent macromolecules, many of which are not unique to the mineralized
tissue, but can be found in other tissues as well (Arias et al.,
2007; Veis, 2003; Wilt and Ettensohn, 2007). There is however one group of glycoproteins that is unique to many
mineralized tissues. These are proteins that are rich in
acidic amino acids, usually aspartic acid (Marin and
Luquet, 2007; Weiner, 1979). Only a few of these proteins
have been sequenced, as there are many technical problems
in purifying and characterizing such highly charged molecules. One of the best characterized is also the one rst
identied (Veis and Perry, 1967), namely phosphophorin
extracted from vertebrate teeth (Veis, 2003). Others from
mollusks have complex domain structures (Sarashina and
Endo, 1998), including in one case long stretches of polyaspartic acid (Gotliv et al., 2005). These proteins are thought
to be the active components of the mineralization process
(Marin and Luquet, 2007). They are relatively well investigated in mollusk shell formation. Some are thought to be
involved in the formation of the disordered precursor
phase, others in the crystal nucleation and growth processes, and others are located within the crystal itself where
at least in the case of calcite, they change the materials
properties of the crystal (Addadi et al., 2006; Berman
et al., 1988; Nudelman et al., 2007). Such structural proteins do not readily crystallize and the crystal structures
of these mineralizing proteins are not yet known. In fact
it seems highly unlikely that they will form crystals, and
therefore 3-dimensional structural information may need
to be obtained by high resolution cryo-tomography in vitried ice and/or by NMR.
Many mineralized tissues fulll mechanical functions
because the presence of mineral causes the tissue to be relatively sti. Thus understanding the relations between
structure and function often refers to mechanical functions,
and this is not easy. Often the structures involved, especially those of the vertebrates, are not only hierarchical
but also gradedthey change in a systematic manner from
one location to another (Tesch et al., 2001). One approach
for gaining insight into structurefunction relations in such
tissues is to take advantage of the array of surface probe
instruments that can provide information on both materials properties and structure at the nanometer level. This
indeed has proved to be a powerful approach (Kinney
et al., 1999; Moradian-Oldak et al., 2000). A problem with
these methods is that it is dicult to integrate the localized
information into understanding how a whole organ such as
a bone or tooth functions. An alternative approach is to

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S. Weiner / Journal of Structural Biology 163 (2008) 229234

monitor how whole organs deform under load, by mapping

the displacements at the nanometer level, and in this way
relate them to the structure. This can be done using various
optical metrology methods (Shahar and Weiner, 2007).
One particularly promising method is electronic speckle
pattern interferometry (ESPI), that provides nano-scale
deformation information on irregular surfaces even when
the object is under water, which is essential for the study
of biological tissues (Zaslansky et al., 2006). It is still however a real challenge to integrate structural information at
the millimeter, micrometer and nanometer scales and relate
this to mechanical properties that are of course the product
of all these structures working synergistically. A signicant achievement in this regard, is the study by Gupta
et al on bone structurefunction relations (Gupta et al.,
2006).
An unexpected discovery in the vertebrate biomineralization eld was that many tissues of mice in which a minor
bone protein, called Matrix Gla Protein (MGP) was
removed, spontaneously mineralized (Luo et al., 1997).
(Gla or c-carboxyglutamic acid is a most unusual amino
acid that resembles glutamic acid, except that it has two
carboxylate groups). Clearly one function of MGP is to
prevent such catastrophic mineralization. It was also
shown that the common serum protein, fetuin, has a similar function (Heiss et al., 2002). The calcium phosphate
mineral in bones and teeth, carbonated hydroxyapatite, is
a relatively insoluble mineral, and there is sucient calcium
and phosphate in vertebrate tissues for them to be saturated with respect to bone mineral. Thus in the absence
of crystal inhibitors, tissues spontaneously mineralize. This
led to the interesting proposal that removal of inhibitors is
the basic requirement for bone to mineralize (Murshed
et al., 2007).
A most unusual aspect of biomineralization is that there
are probably as many non-biologists working in this eld
as biologists. The biological interest in the eld of biomineralization is obviouscells, extracellular matrices, transport, signaling, hormonal control, and many biomedical
implications that have direct bearing on orthopedics, dentistry, urology and more. The interest of the non-biologists
is less obvious. Materials scientists study mineralized tissues in order to gain inspiration for developing new and
better synthetic materials. Paleontologists and archaeologists are interested in this eld because mineralized tissues
make up most of the fossil record and are also major constituents of the archaeological record. We are now currently witnessing a renewed interest in biomineralization
by geochemists interested in reconstructing past climatic
changes. The shock of global warming has resulted in a
major eort to learn the lessons from past changes in climate in order to better predict the consequences of what
is happening today. The reason for this is that the best
records we have of past climates are embedded in the mineralized tissues of animals that lived at dierent times in the
past (Cohen and McConnaughey, 2003; Erez, 2003). Interestingly, it was the prospect of paleoclimatic reconstruction

that led Lowenstam more than 40 years ago to investigate

the teeth of chitons, those mollusks that form the transient
mineral phase ferrihydrite.
What type of questions should the paleoenvironmental
community be asking? Many of them are really state-ofthe-art structural biology questions that center on cellular
architecture. These include cellular involvement in the
uptake of ions from the environment, the transport of ions
through the membrane, the temporary storage of ions in
specialized vesicles within the cell, transport pathways to
the site of deposition and nally the formation of the mineralized tissue itself. It can be predicted that the recent
advances in tomographic reconstructions of cell architecture using cryo-TEM (Medalia et al., 2002) will be most
important, and that they will enjoy the benets of tracking
the electron dense mineral deposits moving through the
system without having to highlight them in any way using
stains and so on. In fact focusing more on the cellular
machinery involved in biomineralization, in addition to
the extracellular and/or intra-, vesicular processes, should
be high on the future work agenda for the biomineralization eld as a whole. This topic, along with many other
topics in biomineralization, is based on a thorough understanding of structure. Structural Biology is thus in many
respects the foundation upon which the eld of biomineralization stands.
Acknowledgments
I thank Lia Addadi and Fabio Nudelman for their help
in preparing this manuscript. I also thank the Minerva
Foundation and the Kimmelman Center for Biomolecular
Structure and Assembly, Weizmann Institute, as well as
Grant RO1 DE006954 from the National Institute of Dental and Craniofacial Research, for nancial support. S.W.
is the incumbent of the Dr.-Trude Burchardt professorial
chair of structural biology.
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